Chapter 7 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Ataxia

Abstract

Ataxia means “lack of order,” and is defined as a cerebellar disorder characterized by disturbances of coordinated muscle activity. Clinically, cerebellar dysfunction manifests as nystagmus, dysarthria, intention tremor, dysdiadochokinesia, dysmetria, and/or gait ataxia [1]. Ataxia can be seen in numerous genetic, degenerative, and acquired diseases. For a consistent terminology and suggested work-up in this chapter, ataxia is phenotypically classified as: intermittent ataxia, chronic (progressive) ataxia, and ataxia with myoclonic epilepsy [2]

Chapter 7 A Phenomenology-Based Approach to Inborn Errors of Metabolism with Ataxia

Bianca M. L. Stelten and Bart P. C. van de Warrenburg

Phenomenology

Etiology of Ataxia

The diagnostic work-up in ataxia can be challenging due to etiological heterogeneity and overlapping phenotypes, which have become even more complex with the increase in the number of genes associated with ataxia. Inborn errors of metabolism (IEMs) represent a large class of rare genetic disorders, with a wide range of symptoms and phenotypes, including ataxia. The clinical phenotype ranges from pure cerebellar dysfunction to mixed patterns with additional or predominant extrapyramidal, pyramidal, or cognitive features. Many of the disorders discussed in this chapter classically present in children, but adult-onset cases are described. Ataxia in IEMs can have an intermittent as well as slowly progressive course. Early symptoms in the neonatal period; later-onset acute or recurrent attacks with symptoms such as coma, ataxia, vomiting, and acidosis; chronic and progressive symptoms (failure to thrive, developmental delay, but most importantly neurological deterioration and psychiatric signs); and specific systemic signs can be suggestive of an IEM [3]. Exacerbation or worsening of symptoms after high protein ingestion, a long period of fasting, concurrent febrile illness or other physical stressors are also suggestive. A positive family history can be an important diagnostic clue [4].

For developing a differential diagnosis, brain MRI is generally one of the initial steps to rule out structural lesions. The genetic episodic ataxias may be mistaken for metabolic disorders presenting with intermittent ataxia. Another important differential diagnosis is intermittent ataxia due to drugs or intoxication, both treatable causes of ataxia [5]. Intermittent ataxias can present, when occurring for the first time, as an acute or subacute ataxia. Especially in children, more common causes such as infectious diseases or post-infectious inflammatory conditions must be excluded.

Inborn Errors of Metabolism with Ataxia

IEMs form a large group of genetic disorders that are mostly due to a single gene defect resulting in dysfunction of production, regulation, or function of enzymes. Most IEMs are associated with other neurological and/or systemic symptoms, and ataxia may not be the dominant feature. Amino acid and organic acid disorders normally present during episodes of stress or fasting. Urea cycle defects often present with intermittent episodes of behavioral disturbances and even coma, associated with hyperammonemia. A slowly progressive course is more suggestive of a peroxisomal or lysosomal disorder. In addition to IEMs caused by mutations in nuclear genes, there are some that are caused by mutations in mitochondrial DNA (mtDNA). The finding of ataxia with hearing loss, and evidence of increased blood lactate, is suspicious of a mitochondrial disorder [6]. Other clinical clues for mitochondrial disorders are multi-organ involvement, ophthalmoplegia, and maternal inheritance. A significant proportion of IEMs are treatable. Most treatments consist of avoidance of certain triggers, dietary restriction/supplementation, vitamin supplementation, or treatment focused at reducing the amount of the substance that is toxic to the nervous system. In some disorders, hematopoietic stem-cell transplantation can be considered. Many treatments prevent or eliminate symptoms when initiated at a young age, emphasizing the need for early diagnosis [6].

Diagnostic Algorithm

An overview of the most common IEMs with ataxia is given in Table 7.1. Treatable disorders are shown in bold, and are discussed in more detail in the text. To provide guidance for the identification of (treatable) IEMs that can manifest with ataxia, a diagnostic algorithm is proposed (Figure 7.1). In the diagnostic work-up, clinical clues (Table 7.2) can be highly suggestive of a certain diagnosis. Brain MRI can be helpful not only for excluding acquired causes of ataxia, but by showing imaging patterns that point to specific genetic causes of ataxia (Table 7.3), for example in Wilson disease and in aceruloplasminemia. Most IEMs are associated with some degree of white matter disease, and in those with ataxia cerebellar atrophy is common. Also the absence of MRI abnormalities, for example in glucose transporter type 1 (GLUT1) deficiency syndrome, holds a diagnostic value. If there are no clinical clues or characteristic brain MRI patterns suggestive for a specific IEM, the next step is metabolic testing, depending on the type of ataxia. Finally, next-generation sequencing (NGS) or further mitochondrial work-up may often be required to reach a final diagnosis.

Table 7.1 Overview of IEMs that manifest with ataxia (treatable disorders are shown in boldface type)

Disorder/IEM	Gene^a	Type of ataxia^b	Neurological features	Other clinical features	Investigations^c	Treatment
Hartnup disease (OMIM 234500)	SLC6A19 (AR)	A	Intellectual disability, ataxia, psychiatric signs	Photosensitive pellagra-like rash	Elevated excretion of amino acids in urine	High-protein diet, nicotinamide to relieve skin manifestations, tryptophan to improve neurological deficits
Maple syrup urine disease (MSUD) (OMIM 248600)	BCKDHA (type Ia, 45%), BCKDHB (type Ib, 35%) and DBT (type II, 20%) (AR)	A	Developmental delay, episodic encephalopathy, ataxia, pyramidal syndrome, peripheral neuropathy, dystonia, epilepsy	Failure to thrive, poor feeding, respiratory failure, vomiting, lethargy, metabolic acidosis, maple syrup odor of urine	Normal to elevated ammonia, normal to low glucose Elevated branched-chain amino acids (isoleucine, leucine and valine) in plasma Elevated branced-chain hydroxyacids and ketoacids in urine Enzyme testing: low BCKDC activity	Dietary restriction of branched-chain amino acids, avoid fasting Thiamine supplementation in thiamine-responsive individuals In acute situations dialysis Frequent monitoring of plasma amino acid concentrations throughout pregnancy
Glutaric aciduria type 1 (GA-1) (OMIM 231670)	GCDH (AR)	A, B	Hypotonia, developmental delay, intellectual disability, acute encephalopathy, dystonia, ataxia, athetosis, epilepsy	Macrocephaly	Normal to elevated levels of carnitine and acylcarnitines in plasma Normal to elevated glutaric acid in plasma and urine Enzyme testing: low glutamate dehydrogenase activity	Low lysine diet, carnitine supplementation, intensified emergency treatment during periods of catabolism
Urocanic aciduria (OMIM 276880)	UROC1 (AR)	A	Intellectual disability, dysarthria, ataxia	–	Elevated urocanic acid and urocanoylglycine in urine.	– (benign course)
Ornithine transcarbamylase (OTC) deficiency (OMIM 311250)	OTC (XLR)	A	Symptoms are similar to that of MSUD Recurrent coma of unknown cause Intermittent episodes of ataxia, headache, vomiting, lethargy, behavioral changes Developmental delay, epilepsy, psychiatric signs	Hyperammonemia, respiratory alkalosis	Elevated serum ammonia concentration during episodes of symptoms Amino acids: to differentiate from amino acid and organic acidemias	Dietary restrictions: low protein, high calorie diet Supplementation with sodium phenylbutyrate, arginine In acute crisis: hemodialysis Periodic blood test for detection of elevated levels of ammonia may allow treatment before clinical symptoms appear
Pyruvate dehydrogenase E1-alpha deficiency (PDH deficiency) (OMIM 312170)	PDHA1 (XLD)	A, B	Hypotonia, epilepsy, ataxia, pyramidal syndrome, peripheral neuropathy Carbohydrate- and fever-sensitive ataxia is suggestive for PHD deficiency	Failure to thrive, metabolic acidosis Facial dysmorphic features: microcephaly, frontal bossing, wide nasal bridge Bilateral optic neuropathy	Elevated lactate and pyruvate, and normal glucose in serum Elevated alanine in plasma Enzyme testing: low activity of the PDH complex	Thiamine supplementation may be effective in the thiamine-responsive form Ketogenic diet Treatment of lactic acidosis with dichloroacetate
Pyruvate carboxylase deficiency, type C (OMIM 266510)	PC (AR)	A	Type A and B manifest in the neonatal period or early infancy as PDH deficiency Type C manifests with relatively benign intermittent ataxia, mild developmental delay, dysarthria, dystonia, epilepsy	Failure to thrive, metabolic acidosis	Mildly elevated lactate and pyruvate, and normal to low glucose in serum Elevated alanine and lysine in plasma and urine Enzyme testing: low PC activity	–
Leigh syndrome (OMIM 25600)	BSL1L, COX 10, COX 15, FOXRED1, NDUFAF, NDUFS3, NDUFS4, NDUFAF6, NDUFS7, NDUFS8, NDUFA10, SDHA, SURF1 (AR/ maternal inheritance)	A,B	Relapsing-remitting course in early childhood, often triggered by concurrent illnesses Ataxia is most common in mitochondrial defects Also hypotonia, pyramidal syndrome, ophthalmoplegia, and epilepsy	Optic neuropathy Respiratory abnormalities: hyperventilation, apnea Cardiomyopathy and conduction defects	Elevated serum and CSF lactate and pyruvate levels.	–
Biotinidase deficiency (OMIM 253260)	BTD (AR)	A,B,C	Hypotonia, developmental delay, (myoclonic) epilepsy, ataxia, pyramidal syndrome In case of partial biotinidase deficiency: symptoms provoked by stress	Erythematous skin rash, alopecia Optic atrophy Deafness Respiratory problems: hyperventilation, stridor	Elevated lactate in plasma Elevated organic acids in urine Enzyme testing: low biotinidase activity in serum	Biotin supplementation
Biotin–thiamine-responsive basal ganglia disease (OMIM 607483)	SLC19A3 (AR)	A	Subacute episodes of encephalopathy, characterized by confusion, external ophthalmoplegia, dystonia, ataxia, pyramidal syndrome, coma	–	Normal to high lactate in serum	Avoiding triggers Treatment with biotin and thiamine
Glucose transporter type 1 (GLUT1) deficiency syndrome (OMIM 606777)	SLC2A1 (AR)	A, B	Cognitive impairment, exercise-induced paroxysmal dyskinesia, dystonia, pyramidal syndrome, epilepsy Ataxia can be the only finding, mimicking other episodic ataxias Ataxia worsens before meals	Microcephaly	Low CSF-to-blood glucose ratio Lumbar puncture in fasting state and determination of blood glucose before the lumbar puncture Low to normal lactate in CSF	Ketogenic or modified Atkins diet
Cerebrotendinous xanthomatosis (CTX) (OMIM 213700)	CYP27A1 (AR)	B	Intellectual disability, epilepsy, pyramidal syndrome, cerebellar syndrome, peripheral neuropathy, extrapyramidal signs Psychiatric manifestations	Chronic diarrhea, bilateral cataract, tendon xanthomas (Achilles tendons) Neonatal jaundice Osteoporosis Atherosclerotic vascular disease	Elevated serum cholestanol, elevated urinary bile alcohols	Chenodeoxycholic acid 750 mg/day (children 15mg/kg per day). HMG-CoA reductase inhibitors can be added.
Abetalipoproteinemia (OMIM 200100)	MTP (AR)	B	Intellectual disability, peripheral neuropathy, myopathy, ataxia, pyramidal syndrome	Failure to thrive, chronic diarrhea, vomiting and steatorrhea in early childhood, intestinal bleeding, retinitis pigmentosa	Acanthocytes in peripheral blood smears Decreased serum, low-density lipoproteins (LDL) and very low-density lipoproteins, increased high-density lipoprotein (HDL) cholesterol levels, low triglyceride levels Low Vitamin A and E in plasma	Diet with reduced fat intake, especially fats that contain long-chain fatty acids Vitamin E supplementation (oral alpha-tocopherol acetate preparation) Vitamin A supplements, and sometimes Vitamin K supplements
Ataxia with isolated vitamin E deficiency (AVED) (OMIM 277460)	TTPA (AR)	B	Ataxia, peripheral neuropathy, pyramidal syndrome, dystonia	Retinitis pigmentosa, cardiomyopathy, pes cavus, scoliosis	High cholesterol and triglyceride levels Low/absent serum Vitamin E	Oral administration of high dose vitamin E
Wilson disease (OMIM 277900)	ATP7B (AR)	B	Tremor, parkinsonism, dystonia, chorea, dysphagia, ataxia, epilepsy, and psychiatric symptoms Rare cases with cerebellar ataxia as presenting symptom have been described	Hepatic disease “Sunflower cataract” Kayser–Fleischer rings of the cornea	Elevated aspartate aminotransferase to alanine aminotransferase (ASAT/ALAT) ratio, low serum ceruloplasmin and copper levels Elevated urinary copper concentrations Increased copper on liver biopsy	Copper chelating agents (D-penicillamine, trientine and tetrathiomolybdate, and/or zinc salts)
Aceruloplasminemia (OMIM 604290)	CP (AR)	B	Ataxia, dystonia, chorea, parkinsonism, cognitive decline	Diabetes mellitus, anemia, iron accumulation in liver	Low hemoglobin, elevated plasma ferritin, low iron plasma, low transferrin, low copper, low ceruloplasmin	Treatment consists of iron chelating therapy and fresh-frozen plasma
Refsum disease (OMIM 266500)	PHYH, PEX 7 (AR)	B	Ataxia, peripheral neuropathy	Anosmia, deafness, ichtyosis, short metacarpals and metatarsals, cardiac arrhythmias and cardiomyopathy Retinitis pigmentosa, subcapsular cataract, acute-angle closure glaucoma	Elevated phytanic acid levels in serum Enzyme testing	Dietary restriction of phytanic acid combined with a high-calorie diet No sudden weight loss Plasmapheresis or lipid apheresis can reduce the plasma concentration of phytanic acid in exacerbations
Niemann–Pick disease type C (NPC) (OMIM 257220)	NPC1, NPC2 (AR)	B,C	Ataxia, vertical supranuclear gaze palsy, pyramidal syndrome, dystonia, loss of speech, (myoclonic) epilepsy, psychiatric signs, cognitive impairment	Neonatal jaundice and hepatosplenomegaly during infancy	Diagnosis is confirmed by biochemical testing of oxysterols and positive Filipin staining in cultured fibroblasts	Miglustat
Recessive ataxia with coenzyme Q10 deficiency (OMIM 612016 /208920 / 613728)	ADCK3, secondary in APTX and ANO10 (AR)	B	Ataxia, peripheral neuropathy, epilepsy, intellectual disability, migraine, psychiatric signs, muscle weakness, hypotonia, upper motor neuron signs, dystonia, chorea, ptosis, ophthalmoplegia	Retinitis pigmentosa, optic atrophy, deafness	Muscle biopsy shows decreased levels of (coenzyme Q10) ubiquinone Plasma concentrations are influenced by dietary uptake and therefor not reliable Normal to elevated lactate	Treatment with ubiquinone (coenzyme Q10)
X-linked adrenoleukodystrophy (X-ALD) (OMIM 300100)	ABCD1 (XLR)	B	Ataxia is not a common feature; typical characteristics: behavioral changes, pyramidal syndrome, peripheral neuropathy, cognitive impairment	Adrenal insufficiency/Addison disease, with diffuse skin hyperpigmentation	High levels of VLCFAs in plasma Monitoring adrenal insufficiency	Dietary restriction of VLCFAs “Lorenzo’s oil” Corticosteroid replacement therapy for patients with adrenal insufficiency Hematopoietic stem-cell transplantation
Metachromatic leukodystrophy (OMIM 250100)	ARSA (AR)	B	Ataxia is often not a presenting symptom; typical characteristics: epilepsy, tremor, peripheral neuropathy, pyramidal syndrome, cognitive impairment	Optic atrophy	Low activity of the enzyme acrylsulfatase Elevated protein in CSF Elevated sulfatides in urine *Caution: “Pseudodeficiencies” due to polymorphism, diagnosis requires high urine excretion of sulfatides or molecular analysis of the ARSA* gene**	Hematopoietic stem-cell transplantation
Krabbe disease (OMIM 245200)	CALC (AR)	B	Ataxia, peripheral neuropathy, pyramidal syndrome, epilepsy Progressive ataxia is more prominent in adolescence	Optic atrophy	Low to absent functional activity of the enzyme beta-galactocerebrosidase Elevated protein in CSF	Hematopoietic stem-cell transplantation (at presymptomatic stage)
Alpha-mannosidosis (OMIM 248500)	MAN2B1 (AR)	B	Intellectual disability, muscle weakness, ataxia, psychiatric signs	Facial abnormalities with macrocephaly, prominent forehead, rounded eyebrow, flattened nasal bridge, widely spaced teeth Skeletal abnormalities (scoliosis and deformation of the sternum) and deafness	Elevated mannose-oligosaccharides in urine Enzyme testing: alpha-mannosidase B	Hematopoietic stem-cell transplantation
Cerebral creatine deficiency syndromes (OMIM 612736/ 612718/ 300352)	GAMT/GATM (AR), SLC6A8 (XLR)	B,(C)	Intellectual disability, (myoclonic)epilepsy, hypotonia, extrapyramidal signs, ataxia	Microcephaly, broad forehead, high palate, prominent nasal bridge, fifth-finger clinodactyly, failure to thrive, vomiting, constipation, hepatitis, mild cardiomyopathy	Guanidinoacetate (GAA), creatine, and creatinine in urine and plasma Molecular testing	Supplementation of creatine, ornithine and dietary restriction of arginine or protein
Cerebral folate deficiency (OMIM 613068)	FOLR1 (AR)	B	Intellectual disability, ataxia, pyramidal syndrome, epilepsy	Hearing loss	Low CSF levels of 5-MTHF	Folinic acid
POLG ataxia	POLG (nuclear gene)	B, C	Ataxia, external ophthalmoplegia, peripheral neuropathy, epilepsy, chorea, dystonia, myoclonus, cognitive impairment	–	Elevated lactate in plasma and CSF	–
L-2-hydroxyglutaric aciduria (OMIM 236792)	L2HGDH (AR)	B	Developmental delay, hypotonia, epilepsy, ataxia, pyramidal syndrome, extrapyramidal signs, behavioral disorders	Macrocephaly	Normal to elevated lysine in plasma and CSF Elevated levels of L-2-hydroxyglutaric acid in urine, plasma, and CSF	–
Congenital disorder of glycosylation, type 1a (CDG-1a, MGAT2-CDG) (OMIM 212065)	PMM2 (AR)	B	Intellectual disability, hypotonia, cerebellar dysfunction, peripheral neuropathy, and extrapyramidal signs Acute neurological events: epilepsy, stroke-like episodes, impairment in consciousness	Failure to thrive, hepatic dysfunction, retinitis pigmentosa, subcutaneous lipodystrophy and inverted nipples	Isoelectric focusing of serum transferrin and enzyme analysis	–
GM2 gangliosidosis (Tay–Sachs/Sandoff disease) (OMIM 272800/268800)	HEXA/HEXB (AR)	B, C	Ataxia, dystonia, motor neuron disease, pyramidal syndrome, cognitive impairment/dementia, (myoclonic) epilepsy and psychiatric symptoms	Optical atrophy, cherry-red spot, macrocephaly	Elevated oligosaccharide in urine Enzyme testing: beta-hexosaminidase A and B activity	–
Neuropathy, ataxia, and retinitis pigmentosa (NARP) (OMIM 551500)	MTATP6 (mitochondrial maternal inheritance)	A, B	Developmental delay and ataxia Muscle weakness and peripheral neuropathy develop later in the disease course Also epilepsy has been described	Retinitis pigmentosa, optic atrophy	Elevated lactate in plasma and CSF	–
PEX10-related peroxisomal biogenesis disorders (OMIM 602859)	PEX10 (AR)	B	Intellectual disability, ataxia, peripheral neuropathy, pyramidal syndrome, extrapyramidal signs.	–	Elevated phytanic acid levels in serum.	–
Succinic semialdehyde dehydrogenase deficiency (OMIM 271980)	ALDH5A1 (AR)	B,C	Developmental delay, hypotonia, encephalopathy, ataxia, (myoclonic) epilepsy, dystonia, myoclonus	–	Elevated 4-hydroxybutyric acid in urine	– (Vigabatrin has shown improvement in single case reports; treatment is mostly symptomatic)
Gaucher disease types 2 and 3 (OMIM 230900/ 231000)	GBA (AR)	(B),C	Ataxia, (myoclonic) epilepsy, pyramidal syndrome, peripheral neuropathy, dementia, ocular apraxia	Hepatosplenomegaly	Glucocerebrosidase enzyme activity	– (Hematopoietic stem-cell transplantation. Enzyme-replacement therapy. Effect on neurological disease remains to be established.)
Neuronal ceroid lipofuscinoses (OMIM 256731/ 601780)	CLN5/CLN 6 (AR)	(B),C	Ataxia, (myoclonic) epilepsy, pyramidal syndrome, behavioral disturbances, Intellectual deficiency	Retinitis pigmentosa	Examination of lymphocytes or skin biopsy demonstrating “curvilinear bodies” Enzyme testing	–
Lafora disease (OMIM 254780)	NHLRC1, EPM2A (AR)	C	Epilepsy (varying from focal visual seizures, to tonic-clonic and myoclonic seizures), furthermore: myoclonus, psychosis, ataxia	–	Skin biopsy to detect “Lafora bodies”	–
Myoclonus epilepsy with ragged red fibers (MERRF) (OMIM 545000)	MTTK, MTTL1, MTTH, MTTS1, MTTS2, MTTF, MTND5 (mitochondrial maternal inheritance)	C	Epilepsy (myoclonic), ataxia, pyramidal syndrome, dementia	Deafness, short stature, optic atrophy, cardiomyopathy with Wolff–Parkinson–White syndrome	Lactic acidosis Ragged red fibers in muscle biopsy	–
Sialidosis type 1 (OMIM 256550)	NEU1 (AR)	C	Ataxia, (myoclonic) epilepsy	Bilateral macular cherry-red spot	Elevated excretion of sialyloligosaccharides in urine Enzyme testing: low neuraminidase activity	–

^a AR, autosomal-recessive; XLR, X-linked recessive.

^b Type of ataxia: A: intermittent ataxia; B: chronic (progressive) ataxia; C: ataxia with myoclonic epilepsy.

^c Next generation sequencing (NGS) or mitochondrial work-up not included.

Table 7.2 Clinical clues suggestive for specific IEMs with ataxia (treatable disorders are shown in bold)

Clinical clues	IEM
*Neurological symptoms*
Macrocephaly	GA-1, L-2-hydroxyglutaric aciduria, GM2-gangliosidosis, alpha-mannosidosis
Microcephaly	PDH deficiency, GLUT1 deficiency syndrome, cerebral creatine deficiency syndromes
Recurrent coma	OTC deficiency, MSUD
Supranuclear palsy	NPC, Gaucher disease type 2 and 3
Exercise-induced paroxysmal dyskinesia	GLUT1 deficiency syndrome
*Systemic symptoms*
Facial dysmorphic features	PDH deficiency, alpha-mannosidosis, cerebral creatine deficiency syndromes
Macula cherry-red spot	Sialidosis type 1, GM2 gangliosidosis
Cataract	CTX, Refsum disease, Wilson disease
Kayser–Fleischer rings	Wilson disease
Retinitis pigmentosa	CDG-1a, abetalipoproteinemia, AVED, Refsum disease, NARP syndrome, recessive ataxia with coenzyme Q10 deficiency, neuronal ceroid lipofuscinoses (i.e. CLN 5/6)
Optic nerve atrophy	PDH deficiency, Leigh syndrome, biotinidase deficiency, recessive ataxia with coenzyme Q10 deficiency, MLD, Krabbe disease, GM2 gangliosidosis, NARP, MERRF
Deafness	Biotinidase deficiency, Refsum disease, recessive ataxia with coenzyme Q10 deficiency, MERRF, alpha-mannosidosis, cerebral folate deficiency
Xanthomas	CTX
Ichtyosis	Refsum disease
Pellagra-like skin changes/photic dermatitis	Hartnup disease
Inverted nipples	GDC-1A
Chronic diarrhea	CTX, abetalipoproteinemia
Neonatal jaundice	NPC, CTX
Hepatosplenomegaly	NPC, Gaucher disease types 2 and 3
Maple syrup odor of the urine	MSUD
Adrenal insufficiency	X-ALD
Diabetes mellitus Anemia	Aceruloplasminemia, mitochondrial diseases Aceruloplasminemia
Cardiomyopathy	AVED, Refsum disease, Leigh syndrome, MERRF, cerebral creatine deficiency syndromes