Martial Mallaret

The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy.

SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.

Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutations: Delineation and Genotype-Phenotype Correlation Study

IMPORTANCE ANO10 mutations have been reported to cause a novel form of autosomal recessive cerebellar ataxia (ARCA). Our objective was to report 9 ataxic patients carrying 8 novel ANO10 mutations to improve the delineation of this form of ARCA and provide genotype-phenotype correlation. OBSERVATIONS The ANO10 gene has been sequenced in 186 consecutive patients with ARCA. The detailed phenotype of patients with ANO10 mutations was investigated and compared with the 12 previously reported cases. The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow. Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity. No patient in our series had peripheral neuropathy. Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy. The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity. Only 2 truncating mutations were reported in homozygosity, one of which (c.1150-1151del) was associated with juvenile or adolescent onset and mental retardation, whereas we show that the presence of at least 1 missense or in-frame mutation is associated with adult onset and slow progression. CONCLUSIONS AND RELEVANCE An ANO10 mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy. We therefore suggest naming this entity autosomal recessive cerebellar ataxia type 3 (ARCA3).

SPG15: a cause of juvenile atypical levodopa responsive parkinsonism

Autosomal recessive hereditary spastic paraplegias with thin corpus callosum (AR HSP-TCC) are rare and complex neurodegenerative disorders characterized by a genetic heterogeneity of which several genes (SPG11 and SPG15, SPG21, SPG47) or loci (SPG32, SPG46) have been identified. In SPG15, additional features have been described [1]: mental retardation, motor neuropathy, dysarthria and pigmentary maculopathy and recently, in a single family with a new homozygous mutation, parkinsonism [2]. In order to further confirm that SPG15 should be considered in the diagnosis of juvenile atypical parkinsonism, we describe another patient affected with SPG15, including juvenileonset levodopa-responsive parkinsonism. A female of Portuguese origin with consanguinity was 17 years old when referred to our center following 12 months of gait difficulties. The patient’s history included mild dysarthria and scholarly delay. Clinical examination demonstrated spastic paraplegia with bilateral extensor plantar reflexes and mild proximal motor deficit in the lower limbs. Vertical saccades were slightly hypometric. By age 19, a left upper limb rest tremor had developed as well as moderate bilateral akinesia, hypertonia, and hypomimia (video). An acute levodopa challenge (250 mg) led to a 60 % improvement of United Parkinson disease rating scale motor score (UPDRSIII) devoted to upper limbs (items 20–25, from 8/24 to 3/24). Rest tremor disappearance was sustained with a levodopa daily dose of M. Anheim and C. Tranchant contributed equally to the work and should be considered as co-last authors.

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1

Importance Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of &agr;-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (&rgr; = −0.532) and elevated AFP levels (&rgr; = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.

Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35

Mutations in the fatty‐acid 2‐hydroxylase (FA2H) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established. We found 5 novel patients (from two families) with mutations in the FA2H gene: none of them showed cerebral iron accumulation (T2‐weighted images performed in all; T2 gradient‐echo in 2); notably, in 1 case, iron accumulation was absent even after 18 years from disease onset on both T2 gradient‐echo and susceptibility‐weight MRI sequences. Cerebral iron accumulation is not a prominent feature in SPG35 and is not always dependent on disease duration; its absence should not discourage from evoking this diagnosis.

Anti-Hu-associated brainstem encephalitis with ganglioneuroblastoma in a young adult

Brainstem encephalomyelitis due to anti-Hu antibodies, directed against intracellular RNA binding proteins (HuD, HuC, Hel-N1 and Hel-N2), may be encountered in paraneoplastic syndrome (PS), or non-PS. In the presence of anti-Hu antibodies, a tumor is found in 83–94 % of cases [1, 2]. Small cell lung carcinoma in adults and neuroblastoma in young children are the most frequent cancer [3]. We report an unusual case of anti-Hu-associated brainstem encephalitis responsible for sensorineural deafness and cerebellar ataxia in a young adult preceding the identification of non-secreting ganglioneuroblastoma. A 19-year-old woman of Caucasian origin with no medical history presented sub-acute, severe bilateral sensorineural deafness (60 dB at 1,000 Hz) leading to a hearing aid. Eight months later, she developed cerebellar ataxia with gait difficulties (SARA score 8/40), downbeat nystagmus, horizontal ophthalmoparesis and dysgueusia. Injected brain MRI revealed enhanced 3rd, 5th, 6th and 7th cranial nerves without brain or cerebellar atrophy (Fig. 1a, b). Extensive laboratory investigations, including accessory salivary gland biopsy, C-reactive protein, antinuclear, anti-gangliosides, anti-thyroperoxydase, anti-cochlea and anti-neutrophil cytoplasmic were negative while anti-Hu antibodies were present in both serum and CSF with oligoclonal bands in CSF. Gynecological examination, mammography, pelvic ultrasonography, total body CT and 18 fluorodeoxyglucose PET scan were normal. Intravenous methylprednisolone (1 g/day for 3 days) followed by 1 mg/kg/day of prednisolone were administered. A month later, intravenous polyclonal immunoglobulins then plasmapheresis were performed, but no clinical advantage except hearing loss improvement (?10 dB). S. Montaut and M. Mallaret contributed equally to the work and should be considered as co-first authors.