Joubert syndrome (JBTS) is a rare autosomal recessive brain disorder characterized by i) absence of cerebellar vermis and ii) presense of "molar tooth sign" (MTS). MTS is formed by abnormal configuration of the superior cerebellar peduncles (SCPs) that connect the cerebellum to the midbrain and thalamus. The most common clinical manifestations include infantile onset of cerebellar ataxia, nystagmus, vertical gaze paresis, ptosis, retinopathy, mental retardation, and episodic hypernea or apnea of the newborn. There is agenesis of cerebellar vermis. Most of the approximately 200 patients reported to date have additional clinical features associated with those of the classical JBTS. The related clinical features define a large spectrum of syndromes with MTS (such as Senior-Löken syndrome), which (together with JBTS) are termed Joubert syndrome related disorders (JSRD) or MTS related syndromes 89. To date, five loci associated with JBTS have been mapped to chromosomes 9q34.3 (JBTS1), 11p11.2-q12.3 (JBTS2), 6q23 (JBTS3), 2q13 (JBTS4), and 12q21 (JBTS5) 10111213. Mutations in the AHI1 gene have been reported in three JBTS3-linked families presenting with a pure cerebellar phenotype 14. Moreover, the NPHP1 gene deletion associated with juvenile nephonophthisis has been identified in subjects affected by a mild form of JBTS 1516. Recently, mutations in the CEP290 gene have been found both in patients with JBTS5 17 and nephronopthisis 18. CEP290 or NPHP6 encodes for nephrocystin-6, a centrosomal protein that modulates the activity of ATF4, a transcription factor implicated in the cAMP-dependent renal cyst formation.

Cayman cerebellar ataxia is another congenital ataxia for which the causative gene has been identified. Individuals with Cayman ataxia have hypotonia from birth, psychomotor delay and non-progressive cerebellar dysfunction, including truncal and limb ataxia, dysarthria, nystagmus, and intention tremor. Imaging studies show cerebellar hypoplasia. The disease has been observed in an isolated population of the Grand Cayman Island; it is caused by mutations in the ATCAY gene 1920. The encoded protein, cayataxin, has a CRAL-TRIO domain. This motif is also found in the α-tocopherol transfer protein that causes ataxia with vitamin E deficiency (AVED).

Ataxia with isolated vitamin E deficiency (AVED) 21 is a hereditary ataxia caused by mutations in the α-tocopherol transfer protein gene, α-TTP 2223. AVED has been described in primary metabolic defects such as abetalipoproteinemia, or secondary to fat malabsortion, chronic cholestasis, pancreatic insufficiency, or cystic fibrosis. In AVED, the unique biochemical abnormality is the very low plasma level of vitamin E, and respectively, the low level of the unique form of vitamin E present in the mammalian serum, RRR-α-tocopherol.

α-TTP is the protein responsible for the specific transfer of vitamin E to the nascent very low-density lipoproteins (VLDL). Patients with AVED have normal vitamin E absorbtion in the intestine, but poor conservation of plasma RRR-α-tocopherol due to impaired secretion of RRR-α-tocopherol in VLDL; thus VLDL represent the primary defect in the pathogenesis of the disease.

AVED is characterized by progressive sensory and cerebellar ataxia usually beginning before age of 20 years (range 2–52 years). Patients with AVED show clinical signs similar to those in Friedreich ataxia, including gait and limb ataxia, dysarthria, lower limb areflexia, loss of vibration and positional sense, and bilateral Babinski sign. In contrast, cardiomyopathy and glucose intolerance are much less frequent, and head titubation and dystonia are observed in some patients only. Diagnosis is based on the finding of low serum vitamin E values (< 2.5 mg/L; normal values 6–15 mg/L) in absence of malabsortion. In contrast to abetalipoproteinemia, AVED patients have a normal lipidogram and normal red blood cell morphology with no acantocytes. Electrophysiological studies show signs of axonal sensory neuropathy with moderate reduction of sensory nerve action potentials (SNAP) and normal motor nerve conduction velocities. Electromyogram is either normal or neurogenic, with polyphasic recordings 2425.

AVED is particularly frequent in countries from the Mediterranean basin and most of cases come from North African populations. The 744delA frameshift mutation is the most frequently found defect and is distributed as a result of a founder effect 23. The most frequent mutation identified in the Japanese population is an amino acid substitution, H101Q, associated with a mild phenotype 2627.

Treatment is based on vitamin E supplements. Administration to adults of 800 mg RRR-α-tocopherol twice daily leads to an increased plasma levels of α-tocopherol and reduction of symptoms and signs.

Abetalipoproteinemia or Bassen-Kornzweig syndrome is an autosomal recessive inherited inborn error of lipoprotein metabolism caused by molecular abnormalities in the microsomal trygliceride transfer protein (MTP), whose gene maps to chromosome 4q22-q24 28293031. The MTP catalyzes the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces. Thus, the assembly or secretion of plasma lipoproteins that contain apolipoprotein B is thought to be the basic pathogenetic defect.

Clinical features include malabsorption syndrome, pigmentary degeneration of the retina and progressive ataxic neuropathy. Red cells show a peculiar "thorny" deformation called acanthocytosis. The neurological symptoms are directly related to the deficiency of liposoluble vitamin E. Total cholesterol is low (<70 mg/dL) and triglycerides are almost undetectable. Lipoprotein profile is characterized by absent low-density lipoproteins (LDL) and VLDL. Symptoms observed in some patients with abetalipoproteinemia are indistinguishable from those of patients with homozygous hypobetalipoproteinemia (HBLP), a codominant genetic disorder characterized by decreased or absent plasma levels of apolipoprotein (apo) B, due to mutations in the apo B gene (chromosome 2p24) 3233 (for review see 34).

Cerebrotendinous xanthomatosis (CTX) or sterol 27-hydroxylase deficiency is an autosomal recessive disorder characterized by defect in bile acid biosynthesis and storage of sterols, and early childhood onset. It has been reported in approximately 200 people worldwide, although the prevalence seems higher in Sephardic Jewish of Moroccan origin 35. Clinical characteristics include xanthomas of the Achilles and other tendons, juvenile cataracts, early atherosclerosis and progressive neurological disorder with cerebellar ataxia beginning after puberty, as well as systemic spinal cord involvement and dementia. Intelligence is low to normal. Large deposits of cholesterol and cholestanol are found in virtually all tissues, particularly in Achilles tendon, brain and lungs. CTX shares some clinical manifestations (including xanthomas and coronary atherosclerosis) with other lipid storage disorders such as familial hypercholesterolemia and phytosterolemia. However, progressive neurologic symptoms, cataracts and mild pulmonary insufficiency distinguish CTX from these two disorders 36.

The disease is caused by mutations in the sterol 27-hydroxylase gene (CYP27) mapped to chromosome 2q33-qter 37. Approximately 40 different mutations of the CYP27 gene have been identified in CTX patients from various populations. Most of mutations are related to the adrenodoxin-binding site and the heme-binding site, although the location of some mutations suggests other putative binding sites to other proteins 38. The CYP27 gene encodes for a mitochondrial cytochrome P-450, which hydroxylates a variety of sterols at C27 position, in association with two protein cofactors, adrenodoxin and adrenodoxin reductase. In the bile acid synthesis pathway, sterol 27-hydroxylase catalyzes the first step in the oxidation of the side chain of sterol intermediates. In CTX, cholestanol (5-alpha-dihydro derivative of cholesterol) has elevated concentrations in all tissues (compared to cholesterol). Diagnosis is made by demonstrating abnormal values of cholestanol in serum and tendons. Plasma cholesterol may be low or normal.

Treatment with cholic acid or chenodeoxycholic acid is indicated. Other treatments include the use of pravastin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, or the combination of both chenodeoxycholic acid and pravastin (for review see 39).

Refsum disease (also named phytanic acid oxidase deficiency, heredopathia atactica polyneuritiformis or hereditary motor and sensory neuropathy IV (HMSN IV), is a rare inherited disorder characterized by defective peroxisomal alpha oxidation of the fatty acids. This defect impairs the metabolism of branched chain fatty acids like phytanic acid (Phyt) and, as a consequence, Phyt accumulates in the blood and other tissues.

The age of onset varies from early childhood to 50 years of age, but most patients have clear-cut manifestations before age of 20 years. The three main clinical features are retinitis pigmentosa, chronic polyneuropathy, and cerebellar ataxia. Most of cases have anosmia, deafness, cardiac arrhythmias, bony and skin abnormalities.

Other peroxisome biogenesis disorders associated with high levels of Phyt are Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata. The first three of them represent a continuum of overlapping features, the most severe being the Zellweger syndrome, and the less severe infantile Refsum disease. Rhizomelic chondrodysplasia punctata is characterized by a distinct phenotype.

Refsum disease is an autosomal recessive trait that is genetically heterogenous. The PHYH (or PAHX) gene placed on chromosome 10pter-p11.2 is responsible for the disorder in most of patients 40. The PHYH gene spans 21 Kb, contains nine exons and encodes for the phytanoyl-CoA hydroxylase (PhyH) that catalyses the first step in the alpha oxidation of Phyt. Thus, in the majority of patients with Refsum disease, PhyH activity is deficient 4142. Different types of mutations have been found distributed along the PHYH gene 43. Recently, Kahlert et al. 44 have suggested that the cytotoxic effect of Phyt seems to be related to a combination of effects on Ca²⁺ regulation, mitochondrial depolarization and increased reactive oxygen species (ROS) generation in brain cells.

A second locus involved in Refsum disease is the PEX7 gene (chromosome 6q21-q22.2) that consists of 10 exons (102 Kb) 4546. To date, only three Refsum patients have been reported with mutations in this gene; mutations in the PEX7 gene have been found causative for other disorders, such as rhizomelic chondrodysplasia punctata 47. PEX genes encode for peroxisomal assembly proteins called peroxins, which are required for the import of matrix proteins into peroxisomes.

Ataxia-telangiectasia (A-T) is a multisystem disease characterized by progressive cerebellar ataxia, oculomotor apraxia, oculocutaneous teleangiectasia, coreoathetosis, recurrent sinopulmonary infections, variable immunodeficiency state with involvement of cellular and humoral immunity, high risk of malignancy (especially leukemia and lymphoma), and enhanced sensitivity to ionizing radioactivity. It is the more common autosomal recessive ataxia after Friedreich ataxia, with an estimated prevalence of 1–2.5/100,000. In most of the cases, the disease begins at age of 2 to 4 years, the first symptom being cerebellar ataxia. Oculomotor signs are present is almost all patients. Teleangiectasias are the second hallmark of the disorder and appear between age of 2 and 8 years. Cerebellar degeneration is progressive until adulthood and patients need a wheelchair by the age of 10. Lifespan is reduced but quality of life has improved and patients survive more than 20 years of age (some of them survive into their 40s and 50s) (for review see 48). Neuropathologic studies show an atrophic cerebellum, predominantly throughout the vermis and less in the lobules. There is reduced number and abnormal arborisation of Purkinje cells, and marked thinning of the molecular layer and granular layer.

Classical complementation experiments on fibroblasts culture from patients suggested that there were a number of genes implicated in the diseases pathogenesis. However, linkage studies showed only one locus on chromosome 11q23 accounting for the disease in different populations 4950. Mutation analysis of the ATM gene has confirmed the genetic homogeneity of A-T. The gene has 66 exons spanning more than 150 kb. A transcript of 12 kb encodes a protein of 3056 amino acids with 370 kDa, which is a member of the phosphoinositol-3 kinase (PI-3K)-like serine/threonine kinases involved in the cell cycle checkpoint control and DNA repair 5152. More than 200 distinct mutations have been reported associated with A-T. Mutations are distributed throughout the entire gene and involve almost all coding exons 53. Most of patients are compound heterozygous for mutations that give truncated proteins, although missense mutations can alter the protein function 54. Some A-T cases have atypical clinical manifestations with a milder phenotype that present one or more of the following symptoms: later onset of the first symptoms, slower progression, longer lifespan, and lower levels of chromosomal instability and cellular radiosensitivity 55. These patients are usually compound heterozygous for a more severe mutation with a milder mutation that makes possible the expression of a small amount of protein 5657. As the majority of patients carry unique mutations, mutation analysis is possible for the clinical diagnosis of A-T. When the mutation is unknown or sequence analysis is not available, prenatal diagnosis is based on linkage analysis using flanking linked markers.

Diagnosis is suspected in young children who show signs of cerebellar ataxia, oculomotor apraxia and telangiectasias of the conjunctivae. Magnetic resonance imaging (MRI) examination shows cerebellum atrophy. Other tests that may support the diagnosis are: serum alpha-fetoprotein is elevated above 10 ng/ml in more than 90% of patients; cytogenetic analysis shows a 7:14 translocation (t [7;14] [q11;q32]) in 5–15% of affected individuals; colony in vitro assay (irradiation of colony formation of lymphoblastoid cells) is a very sensitive test but takes approximately three months and is available only in specialized centres. Mutation analysis (available in specialized laboratories only) deserves a special attention as it is not only useful to confirm the clinical diagnosis but is also useful for carrier detection, genetic counseling and prenatal diagnosis.

Ataxia telangectasia-like disorder (ATLD) is a very rare syndrome that shares similarities with A-T and Nijmegen breakage syndrome. Patients' cells show chromosomal instability, increased sensitivity to ionizing radiation, defective induction of stress-activated signal transduction pathways, and radioresistant DNA synthesis 5859. The causative gene, MRE11A, maps very close to ATM (chromosome 11q), thus only a very detailed linkage analysis would separate ATLD from A-T purely on the basis of genetic data 57.

Ataxia with oculomotor apraxia 1 (AOA1) is characterized by early onset gait ataxia (between 2 and 6 years of age), dysarthria, limb dysmetria (later in disease course), oculomotor apraxia, distal and symmetric muscle weakness and wasting, mild loss of vibration and joint position sense, and slow progression. Some patients show dystonia, masked facies or mental retardation. Laboratory studies show a motor and sensory axonal neuropathy, mild loss of large myelinated axons, cerebellar and brainstem atrophy on MRI, hypoalbuminemia and hypercholesterolemia 6061. The disease has been originally reported in Portuguese 61 and Japanese 62 patients. In Japan, AOA1 seems to be the most frequent recessive ataxia, whereas in Portugal it is the second one, after Friedreich ataxia 63.

The causative APTX gene, located on chromosome 9p13.3, has seven exons and encodes a novel protein, aprataxin 64. Alternative splicing in exon 3 generates two distinct isoforms, the longer transcript encodes for a 342 amino acid protein, while the shorter one encodes a 174 amino acid protein. Aprataxin is a nuclear protein composed of three domains that share homology with the amino-terminal domain of polynucleotide kinase 3'-phosphatase (PNKP), histidine-triad (HIT) proteins and DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and ROS 65. Recently, involvement of aprataxin in the DNA sSSBR-machinery has been demonstrated 66. Thus, AOA1 may be classified within the group of ataxias associated with DNA repair defects. Due to its capacity to interact with proteins involved in DNA repair, aprataxin could influence the cellular response to genotoxic stress 67.

Ataxia with oculomotor apraxia type 2 (AOA2), also referred as non-Friedreich spinocerebellar ataxia type 1 (SCAR1), is an autosomal recessive disorder that represents approximately 8% of non-Friedreich ARCA 68. It is characterized by spinocerebellar ataxia with onset between 11 and 22 years, choreoathetosis, dystonic posturing with walking, and is occasionally associated with oculomotor apraxia, and elevated values of gamma-globulin, alpha-protein and creatin kinase (CK) 68. Cerebellar atrophy is observed in some patients. Electrophysiology studies show absence of sensory potentials.

The causative gene has been mapped to chromosome 9q34. The gene has recently been isolated and characterized 69. It encodes senataxin (SETX), a 2,677-amino acid protein that contains at its C-terminus a classic 7-motif domain found in the superfamily 1 of helicases. Senataxin may act in the DNA repair pathway and also may be a nuclear RNA helicase with a role in the splicing machinery 69. No evidence of chromosome instability or sensitivity to ionizing radiation has been observed in cells from affected individuals. Mutations in SETX gene have been identified also in the autosomal dominant form of amyotrophic lateral sclerosis, known as ALS4 70.

Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a disorder characterized by recessive ataxia with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, and pes cavus and stepagge gait, as described in Charcot-Marie-Tooth disease. Genetic studies in a large Saudi Arabian family mapped the disease to chromosome 14q31 and identified a homozygous mutation in the gene encoding topoisomerase I-dependent DNA damage repair enzyme (TDP1) 71. Patients had history of seizures, mild brain atrophy, mild hypercholesterolemia and borderline hypoalbuminemia.

Xeroderma pigmentosum (XP) is a clinical syndrome with multiple complementation groups and genotypes 72, inherited as an autosomal recessive trait 73. The prevalence in the United States is approximately 1:250,000, and higher frequency is estimated in Japan and the Mediterranean areas 74. XP is characterized by a variable neurological syndrome (including ataxia, choreoathetosis, spasticity, deafness, and progressive mental retardation), skin photosensitivity, early onset skin cancers, telangectasia, photophobia, conjunctivitis, keratitis, ectropion and entropion. It is typical to observe defective DNA repair after ultraviolet damage of culture cells.

The disease is genetically heterogeneous and has been classified into seven complementation groups, XPA-XPG, and each complementation group has a specific entry in the MIM database. Eight genes have been identified among XP patients 72: seven, XPA-XPG, are involved in nucleotide excision repair (NER) and one, the XP variant, is involved in replication of damaged DNA of the leading strand 75.

Friedreich ataxia (FRDA) has been first described by the German pathologist Nicolaus Friedreich in nine members, two females and seven males of three sibships, in a series of five papers between 1863 and 1877 4. The author observed onset around puberty and presence of ataxia, dysarthria, sensory loss, muscle weakness, scoliosis, foot deformity and cardiac symptoms. After description of tendon reflexes by Erb in 1875, Friedreich also recognized the absence of these reflexes as a feature of the disease. For a number of decades, FRDA and the other forms of inherited ataxias have undergone a large debate about their clinical definition and classification. Geoffroy et al. in 1976 76 and Harding in 1981 77 proposed restricted clinical criteria for FRDA diagnosis. Harding defined essential diagnostic criteria including age of onset of symptoms before 25 years, progressive ataxia of limbs and of gait, absent knee and ankle reflexes, extensor plantar responses, dysarthria, and motor nerve conduction velocity >40 m.s^-1 in upper limbs with small or absent sensory action potentials. Most patients also show pyramidal weakness, absence of reflexes in upper limbs, distal loss of joint position and sense in lower limbs, scoliosis and abnormal electrocardiogram suggesting the presence of hypertrophic cardiomyopathy. Other signs are pes cavus, nystagmus, optic atrophy, deafness, and diabetes mellitus or glucose intolerance. Mapping the FRDA locus allowed to define new clinical variants that involved the main clinical criteria. The isolation of the FRDA gene and description of the GAA trinucleotide expansion as the main mutation have allowed to define the clinical picture and the phenotypic variability based on biological markers 787980 (Table 2).

Mitochondrial recessive ataxia syndrome (MIRAS) is caused by mutations in the polymerase γ (POLG) gene, considered to be the replicative polymerase for mitochondrial DNA 151. Most patients with MIRAS have Finnish ancestry but patients from Norway, the United Kingdom and Belgium have also been reported 152153154. All patients are homozygous for the triptophan-to-serine substitution at position 178 (W178S) associated in cis-position with the E1143G polymorphism. The median age of onset is 28 years (range 5–41 years). Clinical picture may be heterogeneous. The most common manifestations include progressive gait unsteadiness, dysarthria, decreased or absent deep-tendon reflexes in the lower limbs, decreased vibration or joint position sense, nystagmus and other eye-movement abnormalities. Epilepsy and neuropathy may be initial features. Some patients may show mild to moderate cognitive impairment, involuntary movements may also be present.

Mutations in POLG gene have been associated with a number of clinical phenotypes. First mutation in this gene was reported in patients with autosomal dominant progressive external ophtalmoplegia (PEO) 155 but mutations have also been identified in patients manifesting Alpers syndrome 156157158, SANDO (sensory ataxic neuropathy, dysarthria, and ophtalmoparesis) 159, and other allelic phenotypes 151152155160161. In fact, there is a POLG syndrome that shows clinical allelic heterogeneity, which in some instances is manifested as an autosomal recessive ataxic syndrome (MIRAS is one of them).

Infantile onset spinocerebellar ataxia (IOSCA), described in Finland, is characterized by a very early onset ataxia (between 1 and 2 years), athetosis and reduced tendon reflexes. Other features such as ophthalmoplegia, hearing loss, and sensory neuropathy with progressive loss of myelinated fibres in sural nerves, appear later in the disease course. Some patients show reduced mental capacity. Patients are wheelchair-bound by teens. Neuroimaging studies reveal cerebellar atrophy. This rare ataxia is caused by mutations in the C10orf2 gene (chromosome 10q22.3-q24.1) encoding Twinkle, a mitochondrial DNA-specific helicase, and a rarer splicing variant Twinky 162. Mutations in this gene have also been reported in individuals with autosomal dominant progressive external ophthalmoplegia 163.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was originally described in the North-eastern regions of Québec, Canada, in families of French ancestry 164. In this area, the incidence at birth and the carrier rate was estimated at 1/1,932 live born infants and 1/22 inhabitants, respectively 164165. Clinical symptoms are early onset (often at the very early age of 12 to 18 months), progressive spastic ataxia of all limbs with paraplegia, increased tendon reflexes, dysarthria, progressive distal wasting, extensor plantar responses, reduced vibratory and positional senses, weak ankle reflexes, and horizontal gaze nystagmus with poor ocular pursuit. Electrophysiological studies show axonal and demyelinating neuropathy. Atrophy of the superior cerebellar vermis is always present. Retinal hypermyelinated fibers have been observed in patients from Québec, but absent in patients from France, Tunisia and Turkey.

The causative gene sacsin, SACS, maps to chromosome 13q11 166167. It contains an unique very large exon of 12.7 kb encoding 11.5-kb transcript 168. Two founder mutations, a single-base deletion at position 6594 (g.6594delT) and a g.5354C>T nonsense mutation, have been reported in individuals from North-eastern Québec. Recently, new mutations have been described in Tunisian 169, Italian 170171, Japanese 172 and Spanish 173 patients. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder with approximately 200 known cases worldwide 174. Disease onset occurs in infancy. Cardinal features of MSS are cerebellar ataxia, congenital cataracts, and retarded somatic and mental development 175. Dysarthria, nystagmus, muscle weakness and hypotonia are frequent symptoms. Areflexia is associated with a demyelinating peripheral neuropathy. Some patients show episodes of rhabdomyolysis with sustained or episodic elevation of serum creatin kinase activity. Hypergonadotropic hypogonadism is a frequently associated feature. Muscle pathology consists of myopathic changes with rimmed vacuoles. Cerebellar cortical atrophy with vacuolated or binuclear Purkinje cells is also observed. It has been suggested that MSS with myoglobinuria and congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndromes are genetically identical, as they both map to chromosome 18qter 176177. In contrast, a locus for classical MSS has recently been assigned to chromosome 5q31 and mutations have been identified in the SIL1 gene (encoding a factor involved in the proper protein folding) 178179180. The loss of SIL1 function results in accumulation of unfolded proteins, which are harmful to the cell.

Diagnosis is based on clinical symptoms. Ophthalmologic examination should be performed to detect cataracts. MRI scan allows investigation of cerebellar atrophy particularly involving the vermis. Muscle biopsy findings are generally non-specific. Prenatal diagnosis with molecular genetic techniques can be performed in families with know mutation. Treatment is symptomatic. Cataracts often require surgical removal to preserve vision. Hormonal replacement therapy may be needed if hypogonadism is present. Physical and occupational therapy are crucial. Patients survive to old age, with varying disability.

Early onset cerebellar ataxia with retained tendon reflexes (EOCARR), or Harding ataxia, was originally described by Harding in 1981 181. More EOCARR cases have been reported later 182183184. Chio et al. 185 described 40 cases diagnosed between 1940 and 1990 in a defined area of North-western Italy. EOCARR is one of the most frequent autosomal recessive ataxias (after Friedreich ataxia and A-T): the estimated point prevalence ratio is 1/100,000 population and the birth incidence rate is 1/48,000 live births. Current data suggest that it is, in fact, a heterogeneous disorder characterized by early onset cerebellar ataxia (in the first or second decade of life) with preservation of deep tendon reflexes 186187.

A locus on chromosome 13q11-12 has been identified in a Tunisian family, in a position where ARSACS has also been mapped. Differential diagnosis should exclude ARSACS (mutation analysis of sacsin gene), and Friedreich ataxia with retained reflexes and slow progression (analysis of the GAA repeat in the FRDA gene).

This is a syndrome characterized by childhood-onset ataxia and cerebellar atrophy, and markedly reduced levels of coenzyme Q₁₀ in muscle biopsies 188. Patients associate seizures, developmental delay, mental retardation and pyramidal signs. The pattern of inheritance is thought to be autosomal recessive 189190. Supplementation with high dose of oral coenzyme Q₁₀ may improve the clinical picture 190. Recently, a homozygous mutation in the aprataxin gene in a family with coenzyme Q₁₀ deficiency and cerebellar ataxia has been reported 191, suggesting also that coenzyme Q₁₀ may participate in the pathogenesis of AOA1.

Posterior column ataxia and retinitis pigmentosa (PCARP) is characterized by early onset in childhood, sensory ataxia with preservation of pain and temperature, absent reflexes, ring scotoma and progressive vision loss leading to blindness 192193194. The locus AXPC1 has been mapped to chromosome 1q31 195.