Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 2

A number sign (#) is used with this entry because autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2) is caused by homozygous or compound heterozygous mutation in the SETX gene (608465) on chromosome 9q34.

Description

Autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 is a neurodegenerative disorder characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, and increased serum alpha-fetoprotein (AFP; 104150). Oculomotor apraxia is a common but inconsistent finding, found in about 50% of patients; hence this disorder is sometimes referred to as 'ataxia-oculomotor apraxia-2' (AOA2) (Moreira et al., 2004; summary by Ichikawa et al., 2013).

Duquette et al. (2005) emphasized that oculomotor apraxia is not a universal finding in this disorder and suggested the name 'spinocerebellar ataxia, autosomal recessive, with axonal neuropathy-2' (SCAN2) to distinguish it from SCAN1 (607250).

For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (208920).

For a discussion of genetic heterogeneity of SCAN, see SCAN1 (607250).

Clinical Features

Bouchard et al. (1980) described a large French Canadian family with an unusual neurologic disorder. The mother had 27 pregnancies; 10 males and 10 females survived. Of these, 3 females and 4 males, ranging in age from 21 to 48, had progressive ataxia, tremor of dentatorubral type, and severe distal amyotrophy consistent with a neuronal form of Charcot-Marie-Tooth disease (see, e.g., 118210). Several of the father's cousins were said to be ataxic and many descendants and relatives were living in the northeastern United States.

Nemeth et al. (2000) identified a family with ataxia-oculomotor apraxia and showed that affected individuals had no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that the disorder in this family was a true primary cerebellar ataxia.

Bomont et al. (2000) studied a consanguineous Japanese family previously reported by Watanabe et al. (1998). Four affected sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and AFP.

Le Ber et al. (2004) reported 18 patients from 6 unrelated families from France, the West Indies, Turkey, Morocco, and Portugal who showed linkage to the AOA2 locus on chromosome 9q34. Mean age at onset was 15 years (range, 10 to 25), which the authors noted was later than that reported for AOA1 (average age, 7 years). All patients had gait ataxia, axial cerebellar symptoms, cerebellar atrophy on MRI, and increased serum AFP. Peripheral sensory neuropathy was present in most patients, manifest as hypo- or areflexia and distal sensory loss. Oculomotor apraxia was only present in 56% of patients, whereas all patients had impaired smooth pursuit and 89% had gaze-evoked nystagmus. Other features included strabismus (in 11% of patients), dystonic posturing of the hands (28%), choreic movements (22%), and head or postural tremor (17%). Six patients had dysphagia. Seven affected individuals from 1 family had pes cavus and scoliosis; all of these patients eventually became wheelchair-bound. All 3 affected women in this most severely affected family had early menopause between ages 21 and 24 years.

Duquette et al. (2005) reported 24 French Canadian patients from 10 families with autosomal recessive ataxia and distal amyotrophy. One of the families had previously been reported by Bouchard et al. (1980). The clinical phenotype was homogeneous, consisting of progressive gait ataxia beginning at an average age of 14.8 years (range, 2 years in 1 patient to 20 years), distal muscle weakness, cerebellar dysarthria, saccadic ocular pursuit, and progressive distal amyotrophy with loss of deep tendon reflexes and vibration sense. Variable features included gaze nystagmus (91% of patients), strabismus (30%), decreased touch sensation (57%), and tremor (57%). None of the patients had oculomotor apraxia as defined by the inability to generate volitional horizontal saccades with preserved reflex eye movements. All patients had increased serum AFP, approximately 5 times normal levels. Motor nerve conduction velocities were slightly decreased and sensory action potentials were absent. Sural nerve biopsies of 2 patients showed chronic axonal neuropathy with loss of large myelinated fibers. Seven patients had isolated cerebellar atrophy and 5 had more extensive pontocerebellar atrophy. Although the disorder was progressive in all patients, there was variably severity: some patients were wheelchair-bound by their twenties, whereas others could still walk short distances in their forties.

Criscuolo et al. (2006) reported 10 patients from 4 unrelated Italian families with AOA2. Three of the families were consanguineous. Mean age at disease onset was 20.3 years (range 3 to 30) and ataxic gait was the presenting symptom. Although the disease progression was generally slow, no patient was able to walk independently by the time of examination (27 to 67 years). Oculomotor apraxia was only present in 2 patients, although 8 had gaze nystagmus. Other common features included limb and trunk ataxia, dysarthria, dysphagia, peripheral neuropathy, and skeletal and foot deformities. One patient had extrapyramidal signs, including choreiform movements of the head and truncal dystonia, and another had head tremor that disappeared with disease progression. Three patients presented with mild mental decline around age 50 years. Postmortem examination of 1 patient who died of heart failure at age 79 years showed reduced overall size of the brain and marked cerebellar atrophy with loss of Purkinje cells. The substantia nigra was normally pigmented, and cortical neurons were normal. There was severe demyelination in the spinal cord. Molecular analysis identified 4 different homozygous pathogenic mutations in the SETX gene in affected members of these families.

Kobayashi et al. (2007) reported 3 adult Japanese sibs, born of consanguineous parents, with onset of slowly progressive cerebellar ataxia in the teenage years followed by distal muscle weakness after age 30 and distal sensory impairment with areflexia. All 3 patients became wheelchair-bound between 39 and 47 years of age. Smooth pursuit was abnormally saccadic and all had nystagmus, but oculomotor apraxia was not present. Brain imaging showed marked atrophy of the cerebellar vermis and hemispheres. Sural nerve biopsy showed a marked reduction in the number of myelinated and unmyelinated fibers, and electrophysiologic studies were consistent with an axonal sensorimotor peripheral neuropathy. Although Kobayashi et al. (2007) reported normal levels of serum AFP, Ichikawa et al. (2013) found increased levels of serum AFP in a stocked serum sample of 1 of the patients.

Bassuk et al. (2007) reported an African American mother and daughter with a restricted form of AOA2 resulting from 2 SETX mutations in cis on the same allele (608465.0010). The mother and daughter were first evaluated for frequent falling at the ages of 13 and 3 years, respectively. Both also had tremor and oculomotor defects at that time. By age 30, the mother had developed dysarthria, increased tremor, head tremor, ataxic gait, and cerebellar atrophy on imaging studies. Both mother and daughter had increased serum IgG. However, neither showed peripheral neuropathy or head thrusting with horizontal eye movements, which are classic features of AOA2. Bassuk et al. (2007) postulated that the 2 mutations acted synergistically, leading to a dominant-negative mutant protein with partial function and an incomplete phenotype.

Anheim et al. (2008) reported 7 patients with AOA2 from 4 unrelated families. The phenotype was homogeneous and included teenage onset of progressive cerebellar ataxia and areflexia. All 4 patients specifically tested showed axonal neuropathy and diffuse cerebellar atrophy. Five patients needed assistance walking. Only 1 had oculomotor apraxia; 2 had mild dystonia in the lower limbs. All patients and 5 of 8 asymptomatic heterozygotes showed increased serum AFP. Molecular analysis identified 4 pathogenic mutations in the SETX gene (see, e.g., 608465.0013).

Anheim et al. (2009) retrospectively analyzed 90 patients from 15 families with a genetically confirmed diagnosis of AOA2. The patients originated from 15 countries, and 25 novel SETX mutation were identified. The median age at onset was 14 years. Clinical features included polyneuropathy (97.5% of patients), cerebellar atrophy (96%), occasional oculomotor apraxia (51%), pyramidal signs (20.5%), head tremor (14%), dystonia (13.5%), strabismus (12.3%), and chorea (9.5%). Other features included pes cavus and increased serum AFP. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations outside of the helicase domain and deletion and nonsense mutations. Anheim et al. (2009) suggested that the lack of pyramidal signs in most patients may have resulted from severe motor neuropathy.

Hammer et al. (2012) reported 13 patients, ranging in age from 16 to 30 years, from 5 consanguineous Tunisian families with AOA2 confirmed by genetic analysis. The patients had a relatively homogeneous phenotype, although it varied in severity. Cerebellar ataxia and dysarthria were constant findings. Two patients became wheelchair-bound in their twenties. Various ocular signs included oculomotor apraxia (9 patients), nystagmus (6 patients), saccadic pursuit (4 patients), and lateral gaze with intermittent diplopia (2 patients).

Mapping

By linkage analysis and homozygosity mapping, Nemeth et al. (2000) localized the ataxia-oculomotor apraxia disease locus in their family to a 15.9-cM interval on chromosome 9q34.

Bomont et al. (2000) found linkage of the disorder in a Japanese family to chromosome 9q33.3-q34.3. Genotyping of 2 unrelated Japanese patients from first-degree consanguineous parents showed that one was homozygous for the same region but did not share the biochemical features.

Moreira et al. (2004) identified 9 families with ataxia linked to 9q34 by homozygosity mapping. As most affected individuals had both oculomotor apraxia and elevated AFP levels, they assumed that they were affected by the same disorder, which they had named AOA2. They identified distal and proximal recombinations in families with 2 affected individuals, localizing the defective gene underlying AOA2 to a 1.1-Mb interval containing 13 genes and 3 groups of overlapping spliced ESTs.

Molecular Genetics

In affected members of 15 families with either AOA or ataxia with elevated AFP levels, Moreira et al. (2004) identified 15 different disease-associated mutations in the SETX gene (see, e.g., 608465.0001-608465.0005). All patients had either homozygous or compound heterozygous mutations, consistent with autosomal recessive inheritance.

In affected members of 10 French Canadian families with ataxia, distal amyotrophy, and peripheral neuropathy, Duquette et al. (2005) identified mutations in the SETX gene. One of the families had been reported by Bouchard et al. (1980). A founder mutation (L1976R; 608465.0009) was identified in all families.

In 2 Japanese sibs, born of consanguineous parents, with autosomal recessive spinocerebellar ataxia, Asaka et al. (2006) identified homozygosity for 2 mutations in the SETX gene (608465.0011). Three sibs who were heterozygous for the 2 mutations were unaffected.

In 3 Japanese sibs, born of consanguineous parents, with SCAN2, originally reported by Kobayashi et al. (2007), Ichikawa et al. (2013) identified a homozygous truncating mutation in the SETX gene (Q1441X) that segregated with the disorder in the family. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. Functional studies of the variant were not performed.

Population Genetics

Duquette et al. (2005) estimated that the carrier rate of the disease-causing L1976R mutation in the SETX gene was 3.5% in Quebecois of Anglo-Norman origin and 2.1% in the French Canadian population of Gaspesie.

Anheim et al. (2010) found that AOA2 was the second most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients evaluated in Alsace, France. Of 57 patients in whom a molecular diagnosis could be determined, 7 were affected by AOA2. The authors estimated the prevalence of AOA2 to be 1 in 900,000 in this region. Friedriech ataxia (FRDA; 229300) was the most common diagnosis, found in 36 of 57 patients, and ataxia-telangiectasia (AT; 208900) was the third most common diagnosis, found in 4 patients.