In patients with the suspected diagnosis of an ARCA, the available laboratory testing for biomarkers of several ARCA subtypes should be performed (ataxia telangiectasia (AT), AOA2, ataxia with vitamin E deficiency (AVED), ARCA3 (ANO10), Refsum disease, cerebrotendinous xanthomatosis (CTX), Niemann–Pick type C disease (NPC), Wilson disease, abetalipoproteinemia (ABL), ARCA2, ARCA3) – particularly as a treatment exists for some of these metabolic disorders. Several common pathophysiological pathways for ARCA have been described so far, including mitochondrial dysfunction, DNA repair deficiency, abnormal protein folding and degradation, paroxysmal disorders, and recently identified pathologies like a disorder of the endocannabinoid metabolism . Several attempts to classify ARCA have been made according to the transmission (autosomal recessive spinocerebellar ataxias = SCAR) (Fig. 12.1; Table 12.1), while certain ARCA were subsumed due to the clinical picture (spastic ataxia = SPAX) (Fig. 12.1; Table 12.2). However, the ARCA classification is confusing because of similarity to other neurodegenerative movement disorders such as HSP. The reason why some HSP are not classified as SPAX and vice versa is not obvious.
Association between the ARCA, SCAR, and SPAX classifications. SPG39: hereditary spastic paraplegia type 39 is allelic with mutations in the PNPLA6 gene, causing BNS
Spastic ataxias according to the spastic ataxia (SPAX) classification
In the following chapter, the ARCA are classified according to their associated pathology in the peripheral nervous system. Three different groups are presented (Table 12.3): (1) ARCA with pure sensory neuropathy, (2) ARCA with motor and sensory polyneuropathy, and (3) ARCA without polyneuropathy.
ARCA according to the associated involvement of the peripheral nervous system
Ataxia without neuropathy
(Pure cerebellar ataxia, possibly associated with other symptoms)
Pure cerebellar ataxia, late onset, tendon reflexes⇑
Epilepsy, myoclonus, mental retardation, stroke-like syndromes, tendon reflexes⇑
Muscle and/or fibroblasts:
Cerebellar ataxia, UMN
Skin/muscle biopsy, blood:
8 months–49 y
Cerebellar ataxia, UMN, intellectual deficiencies, hypogonadism
Epilepsy, mental retardation
Bilateral congenital cataract, myopathy, developmental delay
Creatine kinase ⇑
Supranuclear ophthalmoplegia, splenomegaly, dystonia, cognitive deficits
Leucocytes and/or fibroblasts:
Hepatopathy, dystonia, tremor, parkinsonism, Kayser–Fleischer rings, hemolytic anemia, osteoporosis, protein-losing nephropathy
Ataxia with pure sensory neuropathy
Most frequent ARCA, square wave jerks, sensory neuropathy, UMN, no or only discrete cerebellar atrophy
Ophthalmoparesis, sensory neuropathy, dysarthria, ptosis, myoclonia
Friedreich-like phenotype, retinitis pigmentosa, sometimes head tremor
Vomiting, diarrhea, neonatal steatorrhea
Vitamin A, D, E, K⇓ Abetalipoproteinemia
Cerebellar ataxia with motor and sensory polyneuropathy
(most often < 5 y)
Telangiectasias, oculomotor apraxia, predisposition to cancer and infections, increased radiosensitivity choreodystonic movements
Oculomotor apraxia, choreodystonic movements, increased radiosensitivity
Hypometric saccades, choreodystonic movements, severe motor and sensory polyneuropathy
Oculomotor apraxia, strabismus
Mental retardation, retinitis pigmentosa, spinal and thoracic deformities, epilepsy, cerebellar atrophy
Disturbed serum transferrin by isoelectric focusing
GM2 gangliosidoses with late onset
Spastic paraplegia, dystonia, epilepsy, cognitive disturbance, psychosis, EMG with evidence of anterior horn cell involvement
Hexosaminidase A deficiency (Tay–Sachs)
Hexosaminidase A + B deficiency (Sandhoff)
HEXA (Tay–Sachs)/HEXB (Sandhoff)
HEXA (Tay–Sachs) or
Spastic ataxia, RNFL thickening, axonal and demyelinating polyneuropathy
Demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract, UMN
7 months–50 y
Demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cardiac manifestation
Spastic ataxia, dementia and/or mental retardation, tendon xanthomas, chronic diarrhea, early cataract
Sterol 27 hydroxylase
Spastic ataxia, chorioretinal dystrophy, hypogonadotropic hypogonadism, intellectual deficiency, sensorimotor axonal neuropathy
ARCA with Pure Sensory Neuropathy
Friedreich Ataxia (FRDA)
FRDA is the most common ARCA in Europe, the Middle East, the Indian subcontinent, and North Africa [12, 13]. Its prevalence is estimated to be 1/25,000–1/50,000 in Caucasians, with a carrier frequency of 1/60–1/100 [12, 14]. The most common abnormality in >95 % of FRDA patients is a GAA trinucleotide repeat expansion in intron 1 of the FXN gene, which leads to a loss of function of the corresponding protein frataxin . The penetrance of FRDA is complete when both alleles have full-penetrance GAA repeat (≥70 GAA trinucleotides) or in compound heterozygous patients with a GAA repeat expansion on one allele and a FXN pathogenic variant in the other. Frataxin is an iron-binding protein, predominately located in the mitochondria. The loss of function of frataxin results in mitochondrial respiratory chain dysfunction and elevated oxidative stress . The mean AAO is between 10 and 15 years , but AAO of 2 years and over 70 years has been described . The AAO is inversely correlated with the length of GAA repeats [18, 19]. Disease progression depends on the time since diagnosis, the AAO (faster progression if AAO ≤14 years ) and the GAA repeat length. The phenotype is dominated by a mixed cerebellar and sensory (proprioceptive) ataxia. The sensory part of the ataxia is due to an affected dorsal column and a sensory polyneuropathy that can be seen in nerve conduction studies and the weak or absent tendon reflexes. A number of different neurological symptoms could be associated with FRDA: cerebellar dysarthria, UMN, auditory neuropathy, oculomotor manifestations (fixation instability, square wave jerks, seldom nystagmus), dysphagia, and optic atrophy. Rarely, psychiatric manifestations including cognitive impairment, depression, emotional liability, and schizophrenia-like psychosis are described [20, 21]. The most life-threatening, extra-neurological manifestation is hypertrophic cardiomyopathy (60 % of cases) that usually develops after the neurological symptoms. A correlation between the severity of neurological symptoms and cardiac involvement has not been found . Other extra-neurological symptoms are diabetes mellitus type 1 (30 % of cases) and skeletal deformities (foot deformities, scoliosis). MRI scans reveal thinning of the cervical spinal cord and might also show signal abnormalities in the posterior and lateral columns . It should be noted that cerebellar atrophy is not usually evident on brain CT or MRI imaging, especially early in the disease course (Fig. 12.2) [12, 23]. Several clinical types of FRDA have been described, like Friedreich ataxia with retained reflexes (FARR) [24, 25] despite the sensory polyneuropathy and late-onset Friedreich ataxia (LOFA)  or very late-onset Friedreich ataxia (vLOFA) [27, 28], with an AAO over 25 and over 40 years, respectively, as well as an FRDA dominated by spastic paraplegia .
Cerebellar MRI imaging of different ARCA. (a) Ataxia with oculomotor apraxia type 2 (AOA2) with marked cerebellar atrophy; (b) Friedreich ataxia without obvious cerebellar atrophy; (c) autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) with linear hypointensities in the pons; (d) Niemann–Pick type C disease (NPC): marked cerebellar atrophy
The treatment of FRDA is so far based on physiotherapy, occupational therapy, and speech therapy. Several attempts that have addressed mitochondrial pathogenesis have been promising, but without striking success . A substance with some potential is idebenone, which is structurally related to coenzyme Q10. A number of double blind, placebo-controlled, and open-label trials have tested the clinical efficacy of idebenone (dosage 5–45 mg/kg per day) on neurological and cardiac symptoms in FRDA patients [30–34]. However, the studies led to conflicting results regarding cardiac and neurological outcome, and idebenone is currently not generally recommended in the treatment of FRDA. The same applies to erythropoietin (EPO); several open-label studies reported frataxin upregulation after EPO exposure, but no clinical efficacy has been shown [35, 36].
Ataxia with Vitamin E Deficiency (AVED)
The phenotype of AVED is very similar to FRDA progressive with a progressive sensory and cerebellar ataxia. AVED patients might also present cardiomyopathy, but less commonly than with FRDA. In most cases, the AAO is <20 years, with a slower disease progression than FRDA. Decreased visual acuity or retinitis pigmentosa may manifest early in the disease course. Interestingly, head tremor or titubation might be evocative for the diagnosis of an AVED, which resembles a dystonic head tremor. Electrophysiological studies show an axonal sensory neuropathy . AVED is the second most common ARCA after FRDA in North Africa due to a founder effect (744delA frameshift mutation) , but many patients have been reported elsewhere including Europe, North America, and Japan . The laboratory hallmark is the low plasma level of vitamin E (<2.5 mg/l; normal, 5–20 mg/l). The identification of mutations in the TTPA gene confirms the disease. TTPA encodes for the α-tocopherol transfer protein that is implicated in the incorporation of vitamin E into circulating lipoproteins. The mutation results in a reduced delivery of vitamin E to the central nervous system (CNS). The therapy is based on a daily intake of 800–2,000 mg vitamin E, resulting in slower disease progression and probably a slight improvement of neurological symptoms.
ABL, or Bassen–Kornzweig disease, is caused by an error of lipoprotein metabolism due to mutations in the microsomal triglyceride transfer protein gene (MTP) . MTP plays a role in assembly or secretion of plasma lipoproteins that contain apolipoprotein B . The clinical features therefore consist of a malabsorption syndrome due to a reduction of the lipid-soluble vitamins A, D, E, and K, cholesterol, and triglycerides, the absence of apolipoprotein B, and elevated serum transaminases with hepatomegaly due to hepatic steatosis . ABL is a rare ARCA that usually starts in the perinatal period with diarrhea and vomiting and an insufficient gain in weight . In the peripheral blood film acanthocytes and in the ophthalmological examination, retinitis pigmentosa might be found. The neurological symptoms often appear later in childhood and adolescence and comprise hyporeflexia, reduced proprioception, and vibratory sensation, muscle weakness, mild sensory neuropathy in the EMG, and a Friedreich-like ataxia, especially when the patients are not supplemented with vitamin E [43, 44]. The treatment for ABL is based on dietary modification and replacement of lipid-soluble vitamins (Table 12.4) .
Recommended intake of lipid-soluble vitamins in ABL 
Infantile-Onset Spinocerebellar Ataxia (IOSCA)
IOSCA is a rare ARCA that has initially been described in Finland  but recently also in Turkey , Korea , and England . Between 1 and 2 years of life, following a normal period after birth, patients develop progressive ataxia, hypotonia, loss of deep tendon reflexes, myopathy, and athetosis [47, 49]. Signs of advanced disease include ophthalmoplegia, optic atrophy, epilepsy, and sensory axonal neuropathy [47, 49, 50]; sensory–motor neuropathy has been reported recently . Extra-neurological symptoms might comprise elevated transaminases, sensorineural hearing loss, and female hypogonadism . MRI images have revealed high-signal-intensity areas around the fourth ventricle, the superior cerebellar peduncle, the dentate nuclei, and the symmetric cerebellar cortical atrophy [47, 49]. IOSCA is due to mutations in the nuclear-encoded C10ORF2 gene (Twinkle). Twinkle encodes for a mitochondrial DNA (mtDNA) helicase responsible for the maintenance of mtDNA. Besides the autosomal recessive transmitted IOSCA, heterozygous mutations of Twinkle are associated with autosomal dominant progressive external ophthalmoplegia (adPEO) [51, 52]. A phenotypic overlap between adPEO and ataxia in patients with a heterozygous twinkle mutation has been described .
Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO)
SANDO is frequently caused by homozygous or compound heterozygous mutation in the nuclear-encoded DNA polymerase gamma gene (POLG). Together with the Twinkle protein, the mitochondrial DNA polymerase gamma is responsible for mtDNA replication and repair in the mitochondria of eukaryotic cells. The phenotype of POLG mutations is variable and contains SANDO, spinocerebellar ataxia with epilepsy, Alpers syndrome (hepatocerebral mitochondrial depletion syndrome), mitochondrial recessive ataxia syndrome (MIRAS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), PEO (autosomal dominant and recessive), and others [53–57].
SANDO is dominated by a mixed progressive cerebellar and sensory (proprioceptive) ataxia due to a predominantly sensory axonal neuropathy. The AAO is highly variable, between 15 and 60 years. Epileptic seizures, myoclonia, ophthalmoplegia, extrapyramidal symptoms, a myopathy with ragged red fibers, psychiatric phenomena, and liver failure are infrequently associated with SANDO [53, 58]. Besides POLG, mutations in Twinkle are known to cause the SANDO phenotype . Cerebral MRI in SANDO patients reveals high-signal, sometimes “stroke-like” lesions in different brain regions such as the occipital lobes, deep cerebellar nuclei, thalamus, and basal ganglia [53, 58].
ARCA with Cerebellar Ataxia and Motor and Sensory Polyneuropathy
In this subgroup, ARCA with sensorimotor axonal neuropathy are summarized. The phenotype of cerebellar ataxia is variable and associated with oculocephalic dissociation or oculomotor apraxia (OMA) (AT, ATLD, AOA1, AOA2) or UMN (ARSACS, CTX, PHARC) (Table 12.3). Pathophysiologically, this group frequently contains DNA repair and/or cell cycle control mechanisms. Biomarkers exist for most of these entities, such as alpha-fetoprotein (AFP) (AT, AOA2, and to some extent AOA1), albumin (AOA1), and cholesterol (AOA1).
Ataxia Telangiectasia (AT)
AT commonly starts in early childhood (usually before age five). In certain populations, AT is the second most common ARCA but is much less common than FRDA with an estimated prevalence of 1–2.5/100,000 [12, 37]. OMA appears in a high proportion of patients . Severe choreodystonic movements occur in 90 % of AT patients. The EMG might reveal an axonal motor and sensory polyneuropathy . Brain MRI shows cerebellum atrophy. AT should be taken into account if patients develop oculocutaneous telangiectasias (conjunctivae, ears, mouth cavity) and disturbed endocrinological functions (stunted growth in puberty, delayed secondary sexual characteristics, infertility, type 2 diabetes). The cerebellar symptoms are progressive, and the patients are wheelchair bound around the age of 10 years. The lifespan is reduced due to malignancies or respiratory failure, but some patients survive until the fourth decade of life . Laboratory tests show in almost every case an increase of AFP (200–300 ng/ml; normal <7 ng/ml) and immunoglobulin A and G deficiency. AT patients have an increased risk of recurrent infections (especially sinopulmonary and bronchopulmonary), malignancies (mainly hematological), and enhanced radiosensitivity. Recently, a less severe phenotypic variant with a milder disease course and a later AAO has been reported . The presenting features in these patients were extrapyramidal disorder and choreatic movements . In contrast to the classic phenotype, no immunodeficiency, less frequent endocrinological disturbances, but also a high risk for malignancies were noted . The differences between the classic AT phenotype and these variants are explained by different mutations resulting in preserved small amounts of the responsible ATM gene. ATM encodes a P13kinase (ATM protein) that is involved in DNA repair and/or cell cycle control. In addition to the mutated ATM gene, rearrangements of chromosome 7 and 14 appear in 5–15 % of AT patients . A few observational treatment studies have suggested that betamethasone is effective in AT patients [61–64]. Very recently, a multicenter, single-arm, open-label, phase II clinical trial with long-lasting monthly delivery of low doses of dexamethasone over 6 months led to an improvement of the International Cooperative Ataxia Rating Scale as primary outcome parameter .
Ataxia Telangiectasia-Like Disorder (ATLD)
The phenotype of the very rare ATLD comprises cerebellar ataxia with OMA, choreodystonic movements (mainly of the face and upper extremities), and peripheral neuropathy [66, 67]. ATLD is characterized by later onset and a slower progression than AT . Nevertheless ATLD frequently starts in early childhood with cerebellar atrophy on MRI imaging. As for AT, increased radiosensitivity and increased levels of chromosome aberrations in lymphocytes are known. However, the terminology “AT-like” disorder is confusing, as ATLD has no raised AFP nor reduced immunoglobulin levels. For the cancer prone, conflicting results exist [66, 69–71]. ATLD is caused by mutations in the MRE11 gene that codes for a protein with nuclease and intrinsic DNA-binding activity responsible for DNA repair.
Ataxia–Oculomotor Apraxia (AOA1 and AOA2)
The AAO of AOA1 is frequently from early childhood to adolescence (mean 7 years) , but AOA1 patients with a later AAO up to 40 years have been reported [73, 74]. AOA1 is the most frequent ARCA in Japan and is diagnosed in about 10 % of ARCA with an AAO less than 25 years in Europe . The dominant clinical findings are cerebellar ataxia, mental retardation, and motor and sensory polyneuropathy [72, 75, 76]. The phenotype might also comprise choreodystonic movements (maybe only in early disease stages) and muscle weakness . The OMA has been seen in more than two-thirds of patients . The motor and sensory polyneuropathy can be particularly severe and might mimic Charcot–Marie–Tooth disease . The time until wheelchair dependency ranges from 5 to 20 years . Reduced levels of albumin and elevated levels of cholesterol in the serum, and decreased muscle CoQ10 levels in some cases, have been reported as biomarkers. The serum AFP is normal [72, 74, 76–78]. AOA1 patients show marked cerebellar atrophy in MRI [12, 72] and are generally confined to a wheelchair at around 18 years. The causative gene APTX and its protein aprataxin are ubiquitously expressed [2, 79]. APTX acts in an RNA–DNA damage response [80, 81].