Movement Disorders

Cerebellar ataxias are investigated in a rationale manner by the use of an algorithm that includes mode of inheritance and MRI pattern of atrophy:

MSA, anti-GAD cerebellar ataxia, gluten ataxia (celiac disease due to antigliadin antibodies), Miller-Fisher syndrome, paraneoplastic cerebellar degeneration, CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome), and ILOCA are sporadic entities considered in the differential of adult-onset ataxias. MSA is the most common sporadic degenerative ataxia. ARSACS: Spastic ataxia of Charlevoix-Saguenay; AOA1,2,4: Apraxia-oculomotor apraxia; CTX: cerebrotendinous xanthomatosis; FRDA: Friedreich ataxia; SPG7: spastic paraplegia type 7; SANDO: sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia.

Inherited Ataxias With Identifiable Biochemical Errors

Disorder	Clinical Clues	Tests	Treatment
Episodic Ataxias (Except Channelopathies EA-1, EA-2)
Urea cycle defects: OTC deficiency	Encephalopathy, ophthalmoplegia, episodic headache	↑ NH3, orotic acid, ↓citrulline	Protein restriction, benzoate
X-linked ataxia with lactic acidosis	Dysarthria and lethargy triggered by infection/stress	↑Lactate between attacks; ↑Pyruvate during attacks	Thiamine, high-fat diet, acetazolamide
Intermittent maple syrup urine disease	Brain edema, occ. ophthalmoplegia, ketoacidosis	BCAA and BCKA in urine, ↓BCKA dehydrogenase	Thiamine BCAA-free diet
Hartnup disease	Photosensitive rash and headache	Tryptophanuria, aminoaciduria	Nicotinamide
Chronic Ataxias
Multiple carboxylase deficiency	Rash, recurrent ketoacidosis, motor regression	↑ Propionate, ↑glycine, ↓ biotin	Biotin
Biotinidase deficiency	Rash, alopecia, seizures, DD, hyperventilation	↑ Pyruvate, ↑ CSF > serum lactate, ketoacidosis	Biotin
Hypertryptophanemia	Rash (pellagra-like), MR, ataxia	↑ Tryptophan	Tryptophan-free diet
Vitamin E deficiency	FA phenotype, retinitis pigmentosa	α-Tocopherol level (mutation in Chr 8)	Vitamin E
Abetalipoproteinemia	FA phenotype, retinitis pigmentosa	Vitamin E, β-lipoprotein acanthocytes, low cholesterol	Vitamin E
Vitamin B₁₂ deficiency (pernicious anemia)	Sensory ataxia, Romberg sign	Megaloblastic anemia, B₁₂ level, homocystinuria	Cobalamin
Refsum disease	Deafness, polyneuropathy, retinitis pigmentosa	↑ Phytanic acid	Restrict dietary phytanic acid
CTX: Cerebrotendinous xanthomatosis	Cataracts, spasticity, tendon xanthomas	↑ Cholestanol	Chenodeoxycholic acid
Coenzyme Q10 deficiency (familial cerebellar ataxia)	Cerebellar ataxia, upper motor neuron signs, and seizures and/or myoclonus	CoQ10 in muscle and cultured skin fibroblasts	Coenzyme Q10
Screening tests: lactate, pyruvate, NH₃, vitamin E, lipoproteins, amino acids, urine organic acids, and cholesterol.

Hereditary Ataxias—Autosomal Dominant Inheritance

Chromosome		Mutation	Clinical Features Besides Ataxia
SCA1	6p	CAG expansion Ataxin 1	Spasticity (with bulbar weakness), parkinsonism, dystonia, chorea, and distal amyotrophy (peripheral neuropathy) with late slow saccades (causing ophthalmoparesis).
SCA2 Most common in Asians	12q	CAG expansion Ataxin 2	Upper limb areflexia (peripheral neuropathy). Slow saccades with eventual gaze paresis (pons atrophy). Dementia in early onset. Longer ATXN2 repeats (>32) can be associated with motor neuron disease ALS and SCA2 have overlapping clinical features.
SCA3 (MJD) Most common in Portugal	14q	CAG expansion Ataxin 3	Dystonia, parkinsonism, and hyperreflexia (with bulbar weakness) appear early with slow saccades, areflexia, diplopia, and “bulging eyes” (eyelid retraction) later. In older onset, sensory neuropathy, fasciculations and facial myokymia.
SCA4	16q	Unknown	Sensory neuropathy, proprioceptive loss, generalized areflexia.
SCA5	11p	SPTBN Nonrepeat mutations	Pure cerebellar ataxia (referred to as the “Lincoln family ataxia”).
SCA6 Relatively common in Japan, United Kingdom, and Germany	19p	CAG expansion α-CACNL1A/Cav2.1	Older onset, “benign” course, normal life span. Diplopia and downbeat nystagmus without slow saccades. Parkinsonism, pes cavus, and sphincter disturbance can occur. It is allelic with episodic ataxia type 2.
SCA7	3p	CAG expansion Ataxin 7	Upper motor neuron signs are among first signs. Seizures, dementia, and slow saccades with or without supranuclear gaze palsy are common in early onset. Macular degeneration causes visual loss.
SCA8	13q	CTA/CTG expansion ATXN8OS	Relatively pure cerebellar syndrome. Severe truncal titubation is common. Mild athetosis with myoclonic component may be seen. Reduced penetrance suggests an AR disorder.
SCA10 Second most common in Mexico after SCA2	22q	ATTCT expansion ATXN10	Generalized motor seizures occur in some but abnormal EEG in all. Ophthalmologic features include nystagmus and hypometric saccades or even ocular flutter or “dyskinesias.”
SCA11	15q	TTBK2 Tau tubulin kinase	Benign, late-onset cerebellar ataxia with mild upper motor neuron signs.
SCA12 Common in India	5q	CAG expansion	*Head and hand tremor*, associated with upper motor neuron signs and cortical as well as cerebellar atrophy
SCA13	19q	*KCNC3* Kv3.3	Intellectual disability with slow/early ataxia, dysarthria, and hyperreflexia
SCA14	19q	*PRKCG* mutation	Axial myoclonus with tremor of head and limbs in early onset (<27 y); pure cerebellar ataxia in onset >35 y.
SCA15/16 (Allelic)	3p	*ITPR1* IP3 receptor	*Head and hand tremor* in one third of cases; pure cerebellar ataxia with slow and benign course in most
SCA17	6q	*TBP* (TATA-binding protein)	Epilepsy with absence seizures, dementia, parkinsonism, and chorea
SCA18	7q	IFRD1?	Sensory ataxia, pyramidal tract signs, muscle weakness
SCA19/22 (Allelic)	1p	KCND3	Slowly progressive, rare cognitive impairment, myoclonus, hyperreflexia
SCA20	11q	Unknown	Palatal tremor, dysphonia, and dentate nucleus calcification
SCA21	7p	TMEM240	Parkinsonism, postural tremor, hyporeflexia, cognitive impairment
SCA23	20p	PDYN	Dysarthria, bbnormal eye movements, reduced vibration and position sense
SCA25	2p	SCA25	Sensory neuropathy
SCA26	19p	EEF2	Pure ataxia
SCA27	13q	FGF14	Hand tremors in childhood followed by ataxia and cognitive problems
SCA28	18p	AFG3L2	Slow saccades, ophthalmoparesis, and ptosis. Leg hyperreflexia
SCA29	3p	ITPR1	Learning deficits
SCA30	4q		Hyperreflexia
SCA31	16q	BEAN1 (TGGAA expansion)	Pure ataxia, late onset, Japanese ancestry (hearing loss may occur)
SCA32	7q	Unknown	Cognitive impairment and azoospermia
SCA34	6q	ELOVL4	Skin lesions (erythrokeratodermia)
SCA35	20p	TGM6	Hyperreflexia and Babinski signs
SCA36	20p	NOP56	Muscle fasciculations, bulging eyes, tongue atrophy and hyperreflexia (˜MND)
SCA37	1p		Abnormal vertical eye movements
SCA38	6p	ELOVL5	Adult onset and axonal neuropathy, pes cavus
SCA40	14q	CCDC88C	Adult onset, brisk reflexes, and spasticity
SCA41	4q	TRPC3	Pure ataxia
SCA42	17q	CACNA1G	Mild upper motor neuron signs and saccadic pursuit
SCA43	3q	MME	Neuropathy, tremor, and pes cavus
SCA44	6q	GRM1	Hyperreflexia and hypermetric saccades
SCA45	5q	FAT2	Late onset, downbeat nystagmus and dysarthria
SCA46	19q	PLD3	Neuropathy, nystagmus, jerky pursuit, square-wave jerks and slow saccades
SCA47	1p	PUM1	Pure ataxia. Rarely: delayed motor development, early-onset ataxia, and short stature
SCA48	16p	STUB1	cognitive decline
ADCADN	19p	DNMT1	Deafness, sensory loss and narcolepsy
DRPLA More prevalent in Asia	12p13	CAG expansion Atrophin 1 (ATN1)	Early onset: progressive myoclonic epilepsy (PME); late onset: ataxia; onset 20-30 y: HD-like or mixed movement disorder (dystonia, tremor, parkinsonism and dementia)
SCA9 was reserved but never assigned. No single clinical feature is exclusively predictive of a given SCA, except for macular pigmentary degeneration in SCA7. In addition, there is significant intrafamilial phenotypic variability in any given SCA. Isolated cerebellar atrophy is most consistent with SCA5, SCA6, SCA10, SCA14, and EA-2. SCA2 and SCA4 have no UMN signs (only LMN). Parkinsonism can arise within SCA2, SCA3, SCA8, and SCA17, or in mild form in SCA6, usually considered “pure” ataxia.
Some SCAs may present with noncerebellar features: SCA2: L-dopa-responsive parkinsonism or motor neuron disease; SCA3: peripheral neuropathy and restless leg syndrome; and SCA14: action myoclonus. Some AD diseases not in SCA classification may present with predominant ataxia: DRPLA, neuroferritinopathy, prion diseases (especially Gerstmann-Straussler-Schenker disease), Alexander disease, and some adult-onset leukodystrophies. SCA1, SCA3/MJD, SCA7, SCA13, and DRPLA may have childhood onset. Anticipation is more prominent in SCA2, 7, 17, and DRPLA. Expanded CAG repeats coding for polyglutamine tracts cause SCA1, 2, 3, 6, 7, and 17. SCA8 and 12 are caused by noncoding expansions in CTG and CAG, respectively. SCA 10, seen almost exclusively in Mexicans, results from an unstable expansion of a pentanucleotide repeat (ATTCT).

Episodic Ataxias

Episodic Ataxia Type 1 Voltage-gated K+ channel gene (*KCNA1*), 12p13	Episodic Ataxia Type 2^a Voltage-dependent P/Q type Ca+ channel (*CACNA1A*), 19p13
Triggered by stress and exertion
Brief paroxysmal cerebellar ataxic episodes	Long (hours to days) paroxysmal cerebellovestibular ataxic episodes
Interictal myokymia may be the only interictal finding	Interictal nystagmus (gaze evoked or downbeat) is characteristic
Paroxysmal kinesigenic choreoathetosis may be associated	Mild permanent gait ataxia may be a long-term residual deficit
Responds to phenytoin and acetazolamide	Responds to acetazolamide
^aEA-2 is allelic with FHM and SCA-6 and has been associated with episodic weakness, migraine, dystonia, epilepsy, and cognitive involvement.

Spastic Ataxias

Autosomal recessive ataxias of Charlevoix-Saguenay (ARSACS), late-onset Friedreich ataxia (LOFA), adrenomyeloneuropathy (AMN), and hereditary spastic paraplegia type 7 (SPG7) are examples of genetic diseases with prominent spasticity and ataxia.

Hereditary spastic paraparesis SPG7 (paraplegin), the second most common HSP-associated genetic variant, can explain nearly 20% of undiagnosed cerebellar ataxias, although almost universally with hyperreflexia and in some cases with mild spasticity.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS, sacsin, 13q11) described first in Quebec and Tunisia has become recognized in every ethnicity. ARSACS causes a combination of spinocerebellar ataxia with slowly progressive spastic quadriparesis, hypermyelinated retinal nerve fibers (retinal striation), and distal amyotrophy due to demyelinating neuropathy. Brain MRI shows superior cerebellar vermis atrophy, pontine linear hypointensities, and (less commonly) bilateral parietal atrophy and thinning of the mid-posterior part of the corpus callosum.

Other hereditary spastic ataxias include some forms of SCAs (mainly SCA1 and SCA3), adult-onset Alexander disease, FAHN (fatty acid hydroxylase-associated neurodegeneration), some forms of hereditary spastic paraplegias (beyond SPG7, SPG11, SPG15, SPG20 and SPG21), autosomal recessive spastic ataxias (SPAX1, SPAX2, SPAX3, SPAX4, SPAX5), adrenomyeloneuropathy, metachromatic leukodystrophy, vanishing whiter matter leukodystrophy, Krabbe disease, and cerebrotendinous xanthomatosis.

Less Common Episodic Ataxias

EA-3	1q42	Adult onset, vertigo, and tinnitus
EA-4		Adult onset; cerebellar pathology documented
EA-5	*CACNB4*	Childhood to adolescent onset
EA-6	*SLC1A3*	Seizures, migraine and childhood onset
EA-7	19q13	Vertigo, weakness, seizures and childhood to adolescent onset
EA-8	1p	Nystagmus, myokymia, mild dysarthria and persistent intention tremor.
Neonatal epilepsy with LOEA	*SCN2A*	Neonatal epilepsy, later-onset episodic ataxia, autism, hypotonia and dystonia
CAPOS syndrome	*ATP1A3*	Cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss. May include alternating hemiplegia
LBSL	*DARS2*	Cerebellar and sensory ataxia, progressive spastic paraparesis, leukoencephalopathy
LBSL: leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. In LBSL there is increased T2W signal in the cerebral and cerebellar white matter and superior and inferior cerebellar peduncles, involving the sensory and corticospinal tracts of the brainstem (trigeminal nerves and mesencephalic trigeminal tracts) and spinal cord (dorsal columns and lateral corticospinal tracts). MRS shows elevated lactate, low NAA, increased myoinositol and mildly elevated choline. An exercise-induced paroxysmal ataxia and areflexia phenotype, responsive to acetazolamide, has been described. LOEA: late-onset episodic ataxia.

Other hereditary sensory ataxias, besides FRDA and AVED (next page), are abetalipoproteinemia, ataxia telangiectasia, AOA1, AOA2, some SCAs (SCA18 is a pure sensory ataxia), and some hereditary neuropathies (CMT 2B, Dejerine-Sottas disease (CMT 1E, HSAN I-IV, and SANDO [sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis]) or MIRAS [mitochondrial due to POLG1 mutations]).

Hereditary Ataxias: Autosomal Recessive Inheritance

(Abetalipoproteinemia, A-T, FA, Juvenile GM2, MLD, Marinesco-Sjögren Syndrome, Ramsay Hunt Syndrome, CACH, Xeroderma pigmentosum, and cerebrotendinous xanthomatosis [CTX] usually have childhood onset)

Friedreich Ataxia

Onset of cerebellar ataxia or scoliosis before the age of 20 years, along with rapid early progression of areflexia, extensor plantar responses, position and vibration loss, skeletal deformities (pes cavus, scoliosis), and absence of ophthalmoplegia and dementia suggest FRDA. Pes cavus or scoliosis in parents should suggest an autosomal dominant ataxia, such as CMT. Late-onset Friedreich ataxia (LOFA) may present a less severe phenotype and retained reflexes. An unstable GAA repeat within the first intron of the frataxin (FXN) gene on chromosome 9q13 causes FRDA. Affected persons have from 81 to over 1,000 repeats in both their alleles (homozygous expansion). When the expansion is heterozygous, the other allele must have a point mutation. Hypertrophic cardiomyopathy and diabetes mellitus develop when GAA repeats exceed 500. Brain MRI shows atrophy of the upper cervical cord with nearly normal cerebellum.

Ataxia with Vitamin E Deficiency

It is an important and reversible cause of the FA phenotype (spinocerebellar degeneration) with or without retinitis pigmentosa but without cardiomyopathy or glucose intolerance. Nystagmus, ptosis, or partial ophthalmoplegia is seen in one-half of the patients. Head titubation is seen in 28% of patients. Although malabsorption is a common reason, the disorder is often caused by a defect in α-tocopherol transfer protein (α-TTP, 8q13), which impairs the incorporation of α-tocopherol into VLDL. Ataxic patients with low vitamin E but no TTP mutations may have VLDLR mutations. The phenotype includes intellectual disability, dysarthria, and strabismus. Treatment with 800 to 900 IU of oral DL-α-tocopherol improves the deficits.

Ataxia-Telangiectasia (ATM Mutation, 11q)

AT is the most common cause of progressive ataxia of childhood, occurring in 1:40,000 births. The childhood (classic) form includes ataxia, ocular and cutaneous telangiectasias, immunodeficiencies (IgA deficiency, recurrent sinopulmonary infections), and endocrinopathies (stunted growth). The slower-progressing adult-onset AT (“variant AT”) may present with neither ataxia nor telangiectasia, but rather dystonia (with DYT6-like prominent cranial, cervical, and brachial involvement), dystonia-myoclonus, or choreoathetosis. Both AT forms manifest peripheral neuropathy and oculomotor apraxia. Vermal cerebellar atrophy may be absent in variant AT. Patients become wheelchair-bound in 8 to 12 years in classic AT and in 15 to 21 years in variant AT. Alpha-fetoprotein (AFP) is elevated in 90% of patients. Routine chromosomal analysis may show rearrangements of chromosomes 7 and 14. Radiation hypersensitivity and increased incidence of lymphoma and lymphocytic leukemia should prompt avoidance of diagnostic X-ray procedures and periodic monitoring for malignancies.

Ataxia-Oculomotor Apraxia 1 (AOA1, APTX Mutation, 9q)

AOA1 is the most frequent cause of pediatric autosomal recessive ataxia in Japan and second most common in Portugal. AOA1 causes early chorea and ataxia, oculomotor apraxia, and, eventually, cerebellar atrophy (rarely, optic atrophy), but unlike AT, patients have an axonal motor and sensory neuropathy (early areflexia and pes cavus) and no mental retardation, telangiectasia, or immunodeficiency. Important findings are hypoalbuminemia, hypercholesterolemia, high LDL, and low HDL.

Ataxia-Oculomotor Apraxia 2 (AOA2, SETX Mutation, 9q)

AOA2 presents with oculomotor apraxia, strabismus, gait ataxia, areflexia, extensor plantar response, and choreoathetosis in late childhood. It is a milder form of ataxia with a later onset (around 15 years) associated with motor and sensory neuropathy with distal weakness and amyotrophy, reaching wheelchair dependence by 30 years of age. High AFP (>20 ng/mL), IgG, IgA, cholesterol and CK levels are common findings.

Ataxia Oculomotor Apraxia 3 (AOA3, PIK3R5 Mutation, 17p)

AOA3 is similar to AOA2 in phenotype without mutations in the SETX gene, described in a Saudi Arabian Family.

Ataxia Oculomotor Apraxia 4 (AOA4, PNKP Mutation, 19q)

AOA4, described in Portuguese families, is a frequent form of AOA. The age at onset ranges from 1 to 9 years, and most patients have ataxia, oculomotor apraxia, and peripheral neuropathy with impaired vibration sense and areflexia. Severe early-onset neuropathy may mimic CMT leading to pes cavus and hammertoes. AOA4 is different from other AOA diseases due to the presence of obesity and severe polyneuropathy. Some patients have laboratory abnormalities of both AOA1 and AOA2, such as hypoalbuminemia and high AFP.

Chediak-Higashi Syndrome (CHS1 Mutation, 1q)

Primarily a disorder of immune (chronic infections from neutrophil granule defect) and dermatologic (oculocutaneous albinism from melanin granule defect) nature, CHS can manifest in adults with cerebellar ataxia, nystagmus, and peripheral neuropathy, with or without dystonia, parkinsonism, or seizures (children often developed a fatal lymphoproliferative phase). The diagnosis requires examination of a peripheral blood smear, which reveals characteristic large granules in the cytoplasm of neutrophils. Bone marrow transplants have been successful in several cases. Aggressive treatment of infections is indicated.

Marinesco-Sjögren Syndrome (SIL1, 5q31)

Cerebellar ataxia, early-onset or congenital cataracts, and intellectual disability with developmental delay are the triad components. Hypotonia, weakness (due to muscle replacement with fat), short stature, motor and sensory neuropathy, hypergonadotrophic hypogonadism, and skeletal abnormalities (scoliosis) also occur. Electron microscopy of muscle shows autophagic vacuoles, membranous whorls, and electron-dense double-membrane structures associated with nuclei.

Refsum Disease (PAHX, 10p)

Due to a deficiency of phytanoyl-CoA hydroxylase (PAHX) which leads to insufficient α-oxidation of phytanic acid, a lipid of exclusive dietary origin, it leads to cerebellar ataxia, retinitis pigmentosa, deafness, ichthyosis, demyelinating sensory motor polyneuropathy, and high CSF protein. Phytanic acid is elevated in urine and serum. Restricting phytanic acid in diet reverses some of the deficits. Cardiac arrhythmia may result in sudden death. Plasma exchange plays a role in acute exacerbations.

Xeroderma Pigmentosum

This disorder consists of microcephaly, intellectual disability, sensorineural deafness, hypogonadism, and erythema, blistering, and scarring on sunlight exposure due to faulty DNA repair, with vulnerability to skin cancer. Ataxia is due to a combination of spinocerebellar degeneration and peripheral neuropathy (DeSanctis-Cacchione syndrome of xerodermic idiocy).

Cockayne Syndrome

Also resulting from defective DNA repair with sensitivity to ultraviolet light, it is recognized by early senility, photosensitivity, cachectic appearance, dwarfism, microcephaly, retinal degeneration, impaired hearing, ataxia, tremor, dysarthria, and basal ganglia calcifications. Morphologically, it must be differentiated from Seckel syndrome (bird-headed and microcephalic persons of short stature from birth), which is not associated with progressive neurologic deterioration.

GM₂ Gangliosidosis (Tay-Sachs Disease) (HEXA Gene, Low Hex A Activity)

This condition is suspected in any child with an apparent spinocerebellar degeneration, especially if there is Ashkenazi Jewish parentage. Activity of hexosaminidase A (Hex A) is deficient. The juvenile variant presents with an FA-like spinocerebellar degeneration syndrome with ataxia, tremor, spasticity, dysarthria, optic atrophy, episodic psychosis, and dementia. The adult-onset variant manifests as an atypical progressive myoclonic encephalopathy or as a spinal muscular atrophy syndrome. The latter includes upgaze limitation from supranuclear gaze palsy, proximal leg weakness and wasting (with evidence of chronic denervation by EMG), and hyperreflexia. Prominent macular cherry-red spot (from GM₂ ganglioside accumulation; also a feature of sialidosis) is only seen in children who, unlike adults, have no residual Hex A activity.

Childhood Ataxia With Diffuse Central Nervous System Hypomyelination (Mutations in eIF2B [Eukaryotic Translation Initiation Factor 2B] 1-5 Genes)

Also known as leukoencephalopathy with vanishing white matter, CACH presents between 1 and 5 years with progressive ataxia and spastic paraparesis with recurrent coma following minor head trauma or infections. The adult-onset form is milder, with a phenotype ranging from headaches to behavioral changes, dementia, and seizures; and ovarian failure in women (“ovarioleukodystrophy”). Brain MRI shows cystic-like periventricular white matter abnormalities without atrophy.

CACH is not TACH: Tremor-ataxia with central hypomyelination, characterized by tremor, motor regression, spasticity, ataxia, dysarthria, abnormal ocular saccades, gaze-evoked nystagmus, and optic atrophy in the same overall age. TACH is caused by POLR3A and POLR3B mutations, also causal in leukodystrophy with oligodontia, 4H syndrome (hypomyelination, hypodontia and hypogonadotropic hypogonadism), and hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.

PNPLA6-related disorders are characterized by cerebellar ataxia with variable spasticity, chorioretinal dystrophy, and hypogonadotropic hypogonadism. The variants are Gordon Holmes (cerebellar ataxia and hypogonadotropic hypogonadism), Boucher-Neuhäuser (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism), Oliver-McFarlane (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, cerebellar ataxia, and hypopituitarism), Laurence-Moon (retinitis pigmentosa, extra digits, spastic paraplegia, hypogonadism, and mental retardation), and spastic paraplegia (SPG39).

Adult polyglucosan body disease (APBD, GSD IV, GBE1 mutations) presents with progressive upper and lower motor neuron signs, sensory neuropathy, cerebellar ataxia, dementia, and neurogenic bladder, especially among Ashkenazi Jews. Spinal cord atrophy is invariable. Sural nerve biopsy shows PAS-positive, diastase-resistant focal enlargements of myelinated fibers known as polyglucosan bodies.

Cerebrotendinous Xanthomatosis

CTX begins in childhood with cataracts and xanthomata of tendon sheaths and lungs. Learning difficulties are followed by dementia, ataxia, spasticity, dysarthria, dysphagia, and polyneuropathy. Tongue protrusion and seizures may occur. The basic defect is in bile acid synthesis with accumulation of cholesterol and cholestanol. Chenodeoxycholic acid, 750 mg daily, reverses partially or totally the corticospinal, cerebellar, and cognitive deficits.

Hereditary Ataxias: X-Linked Inheritance

Menkes Kinky Hair Disease (Trichopoliodystrophy)

This X-linked recessive disorder is characterized by early growth retardation, peculiar hair (sparse, brittle, twisted), dysmorphic face (full, rosy cheeks, and high-arched palate), changes in the metaphyses of the long bones, and cerebral and cerebellar degeneration in boys. Severe neurologic impairment begins at 2 to 3 months of age and progresses rapidly to decerebration. Brain MRI findings include hypomyelination, tortuosity of cerebral arteries, and diffuse atrophy with ventriculomegaly. Defective intestinal absorption of copper is due to mutation in the ATP7A gene coding for an intracellular copper-transporting protein. Low serum copper leads to failure of copper-dependent enzymes, such as cytochrome C oxidase (hypotonia), tyrosine hydroxylase (twisted hair), and dopamine hydroxylase (ptosis and hypoglycemia). If administered early in life, copper histidinate increases life expectancy from 3 to 13 years of age. The diagnosis is based on serum (low) and fibroblasts (elevated) copper levels. The incidence of the disease is 1/300,000 births.

Comparison Between the Two Disorders Arising From Defects in the Membrane-Associated Copper-Transporting ATPase

	Wilson Disease	Menkes Disease
Defect	ATP7B	ATP7A
Genetics	13q, autosomal recessive	X-linked recessive
Prevalence	1:40,000	1:200,000
Gender	Male:female = 1:1	Always boys
Expression	Liver and brain	Everywhere but liver
Onset	6-60 years	Infants or neonates
Pathophysiology	Copper deposition	Copper deficiency

X-Linked Sideroblastic Anemia With Ataxia

Caused by a mutation in ATP binding cassette gene (hABC7, Xq13) that results in mitochondrial iron accumulation (as with Pearson syndrome and Friedreich ataxia), this condition is suspected when motor delay, childhood-onset ataxia, and dysarthria, with or without spasticity, become progressive after the fifth decade. Imaging studies show cerebellar atrophy. The diagnosis rests on the findings of Pappenheimer bodies on blood smear, ring sideroblasts on bone marrow, and increased free erythrocyte protoporphyrin with decreased MCV.

X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal storage disease whereby abnormal function of peroxisomes leads to the accumulation of very-long-chain fatty acids (VLCFA) in the brain and the adrenal glands leading to a predominantly posterior leukodystrophy and Addison disease. Female carriers may express the myelopathic variant (adrenomyeloneuropathy or AMN) of this disorder.

X-Linked Intermittent Ataxia With Lactic Acidosis

This thiamine (B1)-dependent episodic but ultimately progressive disorder presents in infancy as recurrent coma or in early childhood as episodic ataxia, dysarthria, and occasionally lethargy or weakness. When weakness and areflexia develop, nystagmus and other oculomotor disturbances are seen. Episodes may be spontaneous or follow periods of stress, infections, or high-carbohydrate meals. It is caused by a defect in the pyruvate dehydrogenase complex (PDHC), subunit E1, whose activity can be measured in fibroblasts, leukocytes, or muscle. PDHC deficiency has also been associated with Leigh syndrome, mitochondrial myopathies, and lactic acidosis. During attacks, serum lactate and pyruvate are elevated; interictally, only serum lactate is mildly elevated. Thiamine (100-600 mg/d) and high-fat, low-carbohydrate diet are the cornerstones of management. Daily acetazolamide may abort the attacks.

Rett Syndrome (MeCP2, Lethal to Males, Affects 1 in 10,000 Females)

This X-linked dominant disorder is characterized by developmental regression and autistic behavior in girls following a period of normal development during the first 16 to 18 months of life. After this age, head growth decelerates (acquired microcephaly), hand stereotypies replace purposeful hand movements, and autistic features appear. Gait apraxia and truncal apraxia and ataxia, tremor, and seizures follow and the patient may oscillate between hyperventilation and breath-holding spells (with aerophagia during walking). Autism, neonatal hypotonia, and learning disability may also occur. MeCP2 testing can be extended to girls with gene-negative Angelman syndrome and in boys with bipolar disorder or juvenile-onset schizophrenia and mental retardation. A boy with Klinefelter (XXY) syndrome may have classic Rett syndrome. Rett-like disorders include neuronal ceroid lipofuscinosis and ornithine transcarbamylase deficiency.

Comparison Between Rett Syndrome and Infantile Autism

Rett Syndrome	Infantile Autism
Normal development until 7-18 months	Onset from early infancy
Developmental regression	No loss of previously acquired skills
Profound intellectual disability in all functional areas	Differential intellectual function (visual-spatial skills better than verbal skills)
Language always absent but eye contact is present and intense	Peculiar speech patterns with impaired nonverbal communication
Stereotypic hand movements	Stereotypies are complex and varied
Little interest in manipulating objects	Ritualistic and skillful manipulation of objects or sensory stimulation
Hyperventilation with air-swallowing, breath holding, bruxism are common	Hyperventilation, breath holding, and bruxism not common
Chorea and dystonia may be present	Chorea and dystonia not present

Unusual forms of X-linked ataxia can be due to mutations in ATP2B3 (childhood onset associated with hypotonia), CASK (cognitive deficiency, microcephaly, hypotonia, optic nerve hypoplasia), OPHN1 (infantile onset, hypotonia, developmental delay, seizures), and SLC9A6 (infantile onset, intellectual disability and seizures).

Congenital Ataxias

As the cerebellum has the longest period of embryological development of any major structure of the brain (32 days of gestation to 1 year postnatally), it is vulnerable to teratogenic insults longer. Selective vermal hypoplasia may be associated with other midline forebrain deficits such as holoprosencephaly and callosal agenesis, characteristic of Dandy-Walker malformation, Chiari malformations, and Joubert syndrome. Global cerebellar hypoplasia encompasses chromosomal diseases as well as Tay-Sachs disease, Menkes kinky hair disease, some cases of spinal muscular atrophy, and sporadic cases of unknown cause.

Congenital metabolic disorders and specific cerebellar abnormalities:

Vermis: carbohydrate-deficient glycoprotein syndromes (CDGP type 1a)

Dentate nucleus: Leigh syndrome

Global cerebellar: mitochondrial disorders

Cerebellar white matter: cerebrotendinous xanthomatosis (CTX)

Calcification: Cockayne, CTX (cerebellar white matter)

Progressive cerebellar atrophy: Canavan, Menkes, mevalonic aciduria, and hypomyelinating leukodystrophy with hypodontia due to POLR3B or POLR3B mutations are considered in the setting of the “4H” syndrome—hypomyelination, hypodontia, and hypogonadotropic hypogonadism

Joubert Syndrome (9q, 11c, 2q [NPHP1], and 6q [AHI1])

Joubert syndrome is characterized by episodic hyperpnea, retinopathy, abnormal eye movements (oculomotor apraxia and seesaw nystagmus), hypotonia, rhythmic tongue protrusion, and ataxia associated with agenesis of the cerebellar vermis. The associated facial dysmorphic features are large head, prominent forehead, high-arched eyebrows, low nasal bridge, epicanthic folds, anteverted nostrils, open mouth, and tented upper lip.

Joubert syndrome is often associated with retinal and renal involvement and is considered part of the cerebello-oculo-renal syndrome (CORS). The molar tooth sign helps in distinguishing the Joubert syndrome and related disorders (see next page) from other hindbrain malformations such as the Dandy-Walker malformation, cerebellar vermis hypoplasia, pontocerebellar hypoplasia, and rhombencephalosynapsis. Funduscopy and electroretinogram are indicated for patients with cerebellar vermis hypoplasia as Leber congenital amaurosis and colobomas are common.

Joubert Syndrome-Related Disorders

These are a group of recessive congenital ataxias consisting of neonatal hypotonia, dysregulated breathing, oculomotor apraxia, and mental retardation. The common denominator is the presence of the molar tooth sign on brain MRI.

Retinopathy, Polydactyly, Mild or no Renal Involvement	Hepatic Fibrosis and Posterior Coloboma (Retinal or Choroidal)	Retinopathy, Coloboma, and Nephronophthisis (±Renal failure)	Notched Upper Lip, Cleft Palate, and Polydactyly
Joubert syndrome	COACH syndrome	CORS	OFD-VI syndrome
COACH = Cerebellar vermis hypoplasia, Oligophrenia, congenital Ataxia, Coloboma, and Hepatic fibrocirrhosis. OFD-VI = orofacial-digital syndrome type VI; Arima syndrome and Senior Loken syndrome were previous nomenclatures for CORS. Meckel-Gruber syndrome (MKS3) may be part of the JSRD as MTS can be seen in addition to encephalocele, polydactyly, cystic dysplastic kidneys, and hepatic fibrosis. These disorders are known collectively as ciliopathies, due to mutations in genes encoding proteins of the primary cilium, a microtubule-containing extension of the cell membrane essential for the development of many tissues.

Specific Congenital Cerebellar Ataxic Syndromes With Mental Retardation

Gillespie Syndrome	Paine Syndrome
ITPR1 gene (dominant or recessive)	X-linked recessive
Partial aniridia with unreactive and dilated pupils in a hypotonic child	Microcephaly, spasticity, myoclonus, and seizures

Pontocerebellar hypoplasias (PCH) are characterized by early neurodegeneration of the cerebellum and pons with phenotypes including ataxia, cognitive impairment and developmental delay. The brain MRI shows hypoplasia of the cerebellum and the pons.

Congenital disorders of glycosylation (CDG, previously termed carbohydrate-deficient glycoprotein syndromes, CDGP) are a group of hypoglycosylation disorders resulting from defects of N-glycosylation. Phosphomannomutase-2 (PMM2, 16p) is the gene for CDG-Ia, the most common subtype. Diagnosis requires isoelectric focusing (IEF) of transferrin and confirmation of low leukocyte phosphomannomutase activity. The clinical spectrum includes multiple systems, such as:

Neurologic: retinitis pigmentosa, peripheral neuropathy (hypotonia, hyporeflexia), and cerebellar hypoplasia (“neonatal OPCA”)
Cutaneous: inverted nipples, lipodystrophic skin, abnormal distribution of adipose tissue, joint contractures, facial dysmorphism
Visceral: digestive (feeding problems), hepatic (hepatomegaly), cardiac (pericardial effusions), and renal abnormalities (nephrotic syndrome)
Hematopoietic system: hypercoagulable syndrome (low coagulation factors XI, antithrombin III, heparin cofactor II, and proteins C and S are the basis for increased risk for strokes)
Endocrine system: hypothyroidism, hypogonadism, hyperinsulinism, hypoglycemia, and osteopenia
Immunologic system: hypogammaglobulinemia

Acquired Ataxias: Selected Disorders

Anti-GQ1b IgG Antibody Syndrome-Related Ataxias

Miller-Fisher syndrome (GBS variant) consists of rapid-onset external ophthalmoplegia, cerebellar ataxia, arreflexia and albuminocytological dissociation. The antecedent infectious agents may be Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Streptococcus pyogenes. The IgG autoantibodies (anti-GQ1b) bind to the oculomotor nerves and deep cerebellar nuclei.
Bickerstaff brainstem encephalitis applies to an acute syndrome of progressive external ophthalmoplegia, cerebellar ataxia, hyperreflexia, extensor plantar response, and hemihypoesthesia. CSF studies are usually normal. T2W brain MRI may show asymmetric upper brainstem hyperintensities.

Paraneoplastic Cerebellar Degeneration

It must be entertained in any adult patient with acute or subacute progressive nonfamilial cerebellar syndrome. The underlying malignancies are small cell lung cancer (anti-Hu and anti-CV2), breast or ovary (anti-Yo, anti-Ri [breast only]), and Hodgkin lymphoma (anti-Tr). Only mGluR1 (glutamate receptor type 1) and anti-VGCC (voltage-gated calcium channel) antibodies are directed against cell surface antigen and thus have a pathogenic role and may be treated with IVIg or plasmapheresis.

Nonparaneoplastic subacute ataxia due to autoimmune cerebellitis has been reported with antibodies against GAD, mGluR1, CASPR2 (contacting-associated protein 2), and Homer-3. Homer-3 and mGluR1 are predominantly expressed in the dendritic spines of the cerebellar Purkinje cells.

Celiac Disease

Occurring as a malabsorptive syndrome, a neurologic syndrome, or both, celiac disease can present as gait ataxia or peripheral neuropathy or, less commonly, as myopathy, myelopathy, or progressive myoclonic encephalopathy. Dermatitis herpetiformis (itchy blistering skin rash) is a rare cooccurrence. Antigliadin antibodies (IgG with or without IgA; the latter may be deficient) are the usual screening tool for the diagnosis of celiac disease. IgG deamidated gliadin peptide antibodies and IgA antibodies to transglutaminase TG6 are most specific for cerebellar ataxia even when there is no intestinal involvement. Other autoimmune diseases may coexist. Neuropathology shows striking Purkinje cell loss with cerebellar atrophy. Human lymphocyte antigen (HLA) DQ2 is found in 90% of patients; HLA DQ8 is present in the rest. Gluten sensitivity is the basis for recommending a diet free of wheat, barley, and rye.

Neurodegeneration With Brain Iron Accumulation

Fasting tests for iron metabolism include serum iron concentration (SI), total iron binding capacity (TIBC), percentage of transferrin saturation (Tsat = 100 × SI/TIBC), and serum ferritin. High ferritin with high Tsat indicates hemochromatosis but with low Tsat, aceruloplasminemia.

Globus pallidus hypointensity in NBIA: Pattern recognition

Ferritin (like copper and melanin) causes high T1 signal and low T2 signal on brain MRI. Ultra-rare NBIA: CoPAN (CoA synthase protein-associated neurodegeneration; CoASY mutations), FAHN (fatty acid hydroxylase-associated neurodegeneration; FA2H mutations), and Kufor-Rakeb disease (ATP13A2 mutations).

Neurodegeneration with brain iron accumulation 1 (NBIA-1 or PKAN, pantothenate kinase-associated neurodegeneration due to PANK2 gene mutation) is characterized by progressive tremor, rigidity, spasticity, dystonia, hyperreflexia, and facial dystonia with risus sardonicus. Nystagmus, retinitis pigmentosa, and optic atrophy may occur. Pantothenate kinase is essential in CoA biosynthesis, key in fatty acid metabolism. The “eye of the tiger” sign is due to cavitation within the medial globus pallidum. Biopsy shows axonal spheroids and Lewy bodies. A subtype is hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP).

PLA2G6-associated neurodegeneration (PLAN) has infantile-, childhood-, and adult-onset presentations. The former, infantile neuroaxonal dystrophy, manifests as progressive cerebellar ataxia with cognitive and motor regression, dystonia, axial hypotonia, spastic tetraparesis, optic atrophy, and strabismus. Important adult-onset phenotypes are juvenile-onset L-dopa-responsive dystonia-parkinsonism and dementia associated with frontotemporal atrophy and hereditary spastic paraparesis. Iron deposition, when present, is restricted to the globus pallidus and substantia nigra. Cerebellar atrophy is an important diagnostic clue, unique for an NBIA.

Mitochondrial membrane protein-associated neurodegeneration (MPAN, C19orf12 mutations) leads to early upper and later lower motor neuron dysfunction (˜ALS) and prominent neuropsychiatric abnormalities and cognitive impairment evolving into dementia. Optic atrophy is a feature in juvenile onset; parkinsonism in adult-onset. Variable features include dysarthria, dysphagia, stereotypic hand and head movements, and proprioceptive loss. Unique hyperintense streaking between the internal and external globus pallidus (medial medullary sign) is the imaging hallmark.

Beta-propeller protein-associated neurodegeneration (BPAN, WDR45 mutations) is an X-linked disorder affecting predominantly women with infantile-onset seizures (evolving into West syndrome or Lennox Gastaut syndrome), global developmental delay with limited to absent language, ataxia, and autistic behaviors. With age, seizures tend to resolve whereas cognitive decline, dystonia, and parkinsonism (with modest response to levodopa) emerge. T1-weighted MRI shows symmetric hyperintense “halos” surrounding a band of central hypointensity in the substantia nigra.

Fatty acid hydroxylase-associated neurodegeneration (FAHN, FA2H mutations) is associated with childhood-onset spastic quadriparesis, ataxia, and dystonia. T2W brain MRI may show white matter abnormalities and pontocerebellar atrophy. FA2H mutations also cause leukodystrophy and hereditary spastic paraplegia (SPG35).

Neuroferritinopathy (NBIA-2, ferritin light chain gene, FTL1) is a progressive autosomal dominant disorder with 100% penetrance leading to limb and/or action-specific facial or oromandibular dystonia, chorea, or, rarely, parkinsonism. Dystonia tends to become generalized in 20 years. The phenotype may cause aphonia, dysphagia, and subcortical/frontal cognitive dysfunction. Serum ferritin is low. T2* MRI shows spotty hypointensities within the dentate nuclei, red nuclei, substantia nigra, putamen, globus pallidus, and thalami. The presence of the “cortical pencil lining” sign on susceptibility weighted brain MRI is a diagnostic clue. Cavitation in the pallidum, if present, is reminiscent of the “eye of the tiger” sign in PKAN.

Aceruloplasminemia or the absence of ceruloplasmin (homozygous Cp mutations) leads to parenchymal iron accumulation and, in turn, diabetes, retinal degeneration and craniofacial (blepharospasm, grimacing) and cervical dystonia. Ferritin is high but iron is low. Cp is essential for mobilizing ferric iron from reticuloendothelial stores into transferrin. T2WMRI shows uniform involvement of basal ganglia and thalami but without cavitation. Hypoceruloplasminemia (heterozygous Cp mutation) may present with ataxia, dysarthria, and hyperreflexia. Plasma iron turnover requires only 5% of normal Cp, explaining the normal iron homeostasis in Wilson disease.

Woodhouse-Sakati syndrome (WSS; C2orf37 mutations) presents with progressive dystonia, chorea, dysarthria and cognitive impairment in the background of hypogonadism, deafness, alopecia, and diabetes mellitus. Brain MRI shows excessive iron deposition in the nigra and globus pallidus, and diffuse leukoencephalopathy (extensive confluent hyperintensities in the white matter).

Neuroacanthocytosis (Acanthocytosis-Associated Neurological Disorders)

Acanthocytes are found when native blood with saline and heparin (10 U/mL) in a 1:1 ratio create >6.3% spiculated cells. Diagnostic tests include CK and liver enzymes (elevated in ChAc and MLS, see below), phenotyping of Kx and Kell erythrocyte antigens (MLS), lipoprotein electrophoresis, and, according to phenotype, gene analysis for XK (MLS), VPS13A (ChAc), JPH3 (HDL2), and PANK2 (PKAN).

Abetalipoproteinemia (Bassen-Kornzweig disease, microsomal triglyceride transfer protein [MTP] mutation, 4q) is associated with fat malabsorption from early childhood leading to hypotriglyceridemia, hypocholesterolemia and vitamin E deficiency. It can be expressed as progressive spinocerebellar ataxia, peripheral neuropathy, dorsal column degeneration, and retinitis pigmentosa.

HARP syndrome, a variant of pantothenate kinase-associated neurodegeneration (PKAN or NBAI-1; see Iron and neurology), consists of Hypoprebetalipoproteinemia, Acanthocytosis, Retinitis pigmentosa, and Pallidal degeneration, with normal vitamin E levels.

Chorea-acanthocytosis (ChAc, VPS13A gene mutation, chorein protein, 9q) presents with chorea or other movement disorders (including tics, dystonia, and parkinsonism), orofaciolingual dyskinesias with tongue thrusting and lip biting, dysarthria, dysphagia, vocalizations, seizures, frontal-dominant dementia, and axonal polyneuropathy with areflexia. Tongue and lip biting are part of a “feeding dystonia.” Psychiatric features such as depression, anxiety, obsessive-compulsive disorder, and personality disorders are common. CK and liver enzymes are often elevated. Caudate atrophy, as in HD, with high T2W signal in caudate and putamen, is seen in brain MRI. Chorein levels can be measured in peripheral blood using a Western blot assay.

X-linked McLeod syndrome (MLS, XK gene, Xp21) is a nonataxic X-linked acanthocytosis affecting pairs of brothers or nephews and uncles but no male-to-male transmission. MLS presents in the fifth decade as myopathy, axonal neuropathy with areflexia, increased CK, and dilated cardiomyopathy associated with an abnormal Kell blood group antigen expression. A Huntington disease-like phenotype develops in 50% of patients with chorea, subcortical dementia, psychiatric abnormalities and seizures. Caudate atrophy may also be present.

Huntington disease-like 2 (HDL2, JPH3 gene, encoding junctophilin 3 protein) is an autosomal dominant disorder only reported in patients of African ancestry.

GLUT1 mutations can cause paroxysmal exertion-induced dyskinesias with epilepsy, reduced CSF glucose, and hemolytic anemia with acanthocytosis. The dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with acanthocytes from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.

Dystonia

Dystonia refers to action-induced, patterned abnormal postures or repetitive action-specific movements due to cocontractions of antagonistic sets of muscles.

The clinical clues suggestive of dystonia are:

Action induced (caveat: in neurodegenerative disorders, dystonia becomes evident at rest).
Position dependent: some positions enhance the movements more than others.
Task specific: certain tasks elicit or magnify the movements.
Overflow: dystonic movements are activated by actions in remote body parts
Responsive to sensory tricks: movements improves it with closed-loop tactile feedback (Geste antagoniste)

Classification of Dystonia

Excepting DYT3, primary and dystonia-plus disorders are neurochemical, not neurodegenerative. DRD: dopa-responsive dystonia; DYT14 is now considered DYT5/DRD. M-D: myoclonus-dystonia (other genes apply; see later); RODP: rapid-onset dystonia parkinsonism; DYT8, 9/18, and 10 correspond to paroxysmal dyskinesias (see later).

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