Clinical and Molecular Findings of Ataxia With Oculomotor Apraxia Type 2 in 4 Families

Anheim, Mathieu; Fleury, Marie-Céline; Franques, Jérôme; Moreira, Maria-Céu; Delaunoy, Jean‐Pierre; Stoppa‐Lyonnet, Dominique; Kœnig, M.; Tranchant, C.

doi:10.1001/archneur.65.7.958

Cited by 41 publications

(40 citation statements)

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“…26 Sensorimotor axonopathy has been reported in AOA2 by a number of investigators. 3,4,6,11,12,15,22,27 However, as neither electromyographic (EMG) recordings of proximal muscles nor conduction studies of nerves of the proximal segments of the limbs were mentioned in those studies, and as somatosensory evoked potentials were documented only once, 4 it appears those studies did not aim to distinguish axonopathy from neuronopathy.…”

Section: Discussionmentioning

confidence: 99%

“…14 The SETX gene has an open reading frame of 8031 nucleotides and 24 exons. 27 AOA2 has been associated with homozygous 3,4,6,11,12,19,21,23,31 and compound heterozygous 1,12,13,21,31 alterations that cause frameshift, nonsense, and missense mutations, and a restricted form of the disease resulted from two in cis-dominant SETX gene mutations. 5 Missense mutations in the SETX gene that cause ALS 4 cannot be distinguished at present from those that cause AOA2.…”

Section: Discussionmentioning

confidence: 99%

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Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2

et al. 2009

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Two siblings with ataxia with oculomotor apraxia type 2 (AOA2) exhibited electrophysiological findings suggestive of a sensorimotor neuronopathy, and primary ovarian failure was detected in one of them. Genetic analysis disclosed a novel, homozygous frameshift mutation in the senataxin gene, 2755_2756delGT, responsible for a premature stop codon at position 2760. It is suggested that a neuronopathy might cause the neuromuscular disturbance in AOA2, and that ovarian failure should be looked for in female patients with the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2

et al. 2009

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“…Features include onset between ages of 10 and 22 years (age ≤25 years), elevated serum AFP levels, peripheral neuropathy, occasional oculomotor apraxia and progressive cerebellar ataxia 7,8 . On the other hand, ataxia with oculomo- tor apraxia type 1 (AOA1) has different features such as early age at onset, normal serum AFP levels, and hypercholesterolemia and hypoalbuminemia 8 . In AOA2, oculomotor apraxia is an occasional and inconstant finding, while AFP is elevated in almost all patients (even if sometimes it is only in the upper range of normal values).…”

Section: Patientmentioning

confidence: 99%

“…The same study showed that the likelihood of missing a case using this cutoff was 0.23%, while the likelihood that a non-Friedreich ataxia, non-ataxia-telangiectasia ataxic patient might be affected with AOA2 was 46% 9 . Other mutations of SETX have been associated with the autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4) 7,8 . Beyond the AFP level, when considering neuroimaging findings, both AT and AOA2 present cerebellar atrophy.…”

Section: Patientmentioning

confidence: 99%

Alpha-fetoprotein as a biomarker for recessive ataxias

Braga‐Neto

Dutra

Pedroso

et al. 2010

Arq. Neuro-Psiquiatr.

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Alpha-fetoprotein (AFP) is a fetal protein produced in the yolk sac and in the fetal liver. AFP has been implicated in both ontogenic and oncogenic growth disorders 1 . Although the main biologic role of AFP during pregnancy remains controversial to this day, AFP has been related to fetal birth defects and tumors 1 . AFP is recognized as one of the first tumor markers. It was first associated with hepatocellular carcinomas and later to germ cell tumors 2 . The autosomal recessive ataxias, including ataxia-telangiectasia (AT) and ataxia with oculomotor apraxia type 2 (AOA2), belong to a special group of hereditary ataxias with heterogeneous presentation. Simple laboratory studies, like AFP measurement, have been reported to be helpful in the differential diagnosis of ataxias.The purpose of this review is to describe the association of serum AFP with recessive ataxias. We report the clinical and laboratory findings of three patients with a recessive ataxia profile. CASESWe identified two patients with clinical and laboratory features of AOA2 and one patient with AT. Informed and written consent were obtained from all participants. Patient 1A 28-year-old man was seen at the neurology department with a twelve-year history of progressively worsening balance. He had been a normal full-term delivery from consanguineous parents. His intelligence was normal. Over the years, he developed difficulties in writing and speaking. The symptoms progressed slowly over the following years.His neurological examination showed muscle strength 5/5, with absent reflexes. An ataxic gait with mild enlargement of lower-limb basis, considerable staggering and difficulties with half turn were observed. He was unable to perform tandem walk (heel-to-toe). Finger-nose and heel-shin ataxia were evident. He presented clumsiness of fine finger movements. Gaze-evoked horizontal nystagmus, ocular saccadic overshot, ocular apraxia and cerebellar dysarthria were also present. Vibration and position senses were also impaired. Fundoscopy and visual acuity were normal, and there were no telangiectasia.In order to score the cerebellar dysfunction, we used the International Cooperative Ataxia Rating Scale (ICARS). It consists of four parts: postural and stance disorders (7 items; 34 points), limb ataxia (7 items; 8 points), dysarthria (2 items; 8 points), and oculomotor disorders (3 items; 6 points), with a total of 100 points 3 . The patient reached a score of 47.Specific laboratory studies were as follows: albumin: 4.2 g/dl (3.2-5.6 g/dl); total cholesterol: 200 mg/dl (<200 mg/dl); AFP: 9.2 IU/ml (<5.5 IU/ml); vitamin E: 0.5 mg/ dl (0.5-1.8 mg/dl). Routine blood and urine testing, echocardiogram and electrocardiogram (EKG) were all normal. The audiogram showed normal hearing. A genetic study for Friedreich ataxia was negative.Brain magnetic resonance imaging (MRI) revealed atrophy of the cerebellar hemispheres and vermis, with relative preservation of the brainstem and no ab-

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“…5 To date, more than 50 mutations have been identified in AOA2 families worldwide. 1,2,[6][7][8][9][10][11][12] The mutations are distributed across the entire gene, without any specific mutation hot spots. Most of the mutations are frameshift, or nonsense mutations, supporting that a loss of function of SETX is critical for the development of AOA2.…”

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confidence: 99%

A novel nonsense mutation in a Japanese family with ataxia with oculomotor apraxia type 2 (AOA2)

et al. 2009

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We report a 67-year-old Japanese woman with ataxia with oculomotor apraxia type 2 (AOA2). She was born to consanguineous parents and showed a teenage onset, a slowly progressive cerebellar ataxia and sensory-motor neuropathy and an elevated level of serum a-fetoprotein (AFP). All of these clinical features were consistent with typical AOA2. She lacked oculomotor apraxia, as frequently observed in previously reported AOA2 patients. She was homozygous for a novel nonsense mutation, Glu385Ter (E385X), in the senataxin gene (SETX). To our knowledge, this is the fifth Japanese family with genetically confirmed AOA2. The mutations in SETX in Japanese AOA2 families are heterogeneous, except for M274I, which has been found in two unrelated families. More extensive screening by serum AFP followed by molecular genetic analysis of SETX in patients with Friedreich's ataxia-like phenotype may show that AOA2 is more common in Japan than previously thought. Keywords: ataxia with oculomotor apraxia type 2 (AOA2); sensory-motor neuropathy; senataxin; fiber type grouping Ataxia with oculomotor apraxia type 2 (AOA2) is a rare form of autosomal-recessive cerebellar ataxias associated with axonal sensorymotor neuropathy. 1 The disease-causing gene (SETX) encodes a protein, senataxin, with a homology to the fungal Sen1p protein. 2 SETX, which is composed of 2677 amino acids, contains a DNA/RNA helicase domain (1931-2446 amino acids) near the C terminus, and is likely to have important roles in DNA repair and transcription, and RNA processing. [2][3][4] The N-terminal domain (64-593 amino acids) of SETX is considered a putative protein interaction domain essential for proper localization of SETX. 5 To date, more than 50 mutations have been identified in AOA2 families worldwide. 1,2,[6][7][8][9][10][11][12] The mutations are distributed across the entire gene, without any specific mutation hot spots. Most of the mutations are frameshift, or nonsense mutations, supporting that a loss of function of SETX is critical for the development of AOA2.In this study, we describe a 67-year-old Japanese patient with AOA2 who carried a novel homozygous nonsense mutation, Glu385Ter (E385X), in SETX. Consistent with a prolonged clinical course, she showed prominent fiber type grouping in muscle biopsy. This study identifies the fifth Japanese family with genetically confirmed AOA2 2,8,13-15 (H Takashima, personal communication). CASE REPORTThe patient was a 67-year-old Japanese woman, who was born to consanguineous parents and attained normal developmental milestones during infancy. At B17 years old, she began falling frequently while walking. At age 20, she was referred to the hospital because of an unsteady gait. Soon thereafter, she was diagnosed with cerebellar ataxia, and by age 22, she could not walk without assistance. At B40 years old, she began to show speech disturbance and became clumsy with her hands.She had her first extensive medical examinations at age 46. Neurological examination showed horizontal gaze nystagmus and dysarthria, but ...

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Clinical and Molecular Findings of Ataxia With Oculomotor Apraxia Type 2 in 4 Families

Cited by 41 publications

References 15 publications

Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2

Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2

Alpha-fetoprotein as a biomarker for recessive ataxias

A novel nonsense mutation in a Japanese family with ataxia with oculomotor apraxia type 2 (AOA2)

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