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J Neurol (2008) 255:495–501 DOI 10.1007/s00415-008-0707-z
Ludger Schöls Larissa Arning Rebecca Schüle Jörg T. Epplen Dagmar Timmann
Received: 19 April 2007 Received in revised form: 22 June 2007 Accepted: 19 July 2007 Published online: 20 March 2008
L. Schöls, MD (!) · R. Schüle Hertie-Institute for Clinical Brain Research and Department of Neurology Eberhard Karls-University Tübingen Hoppe-Seyler-Str. 3 72076 Tübingen, Germany Tel.: +49-7071/2980445 Fax: +49-7071/294839 E-Mail:
[email protected] L. Arning · J. T. Epplen Human Genetics Ruhr-University Bochum, Germany D. Timmann Dept. of Neurology University of Essen, Germany * Drs. Schöls and Arning contributed equally to this work.
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ORIGINAL COMMUNICATION
“Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2)
■ Abstract Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive, early onset ataxia caused by mutations in the senataxin (SETX) gene. Ocular apraxia and increased levels of alpha-fetoprotein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation family with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle. Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients presented pronounced peripheral neuropathy with wasting of hand and leg muscles resembling distal motor neuronopathy. Increased alphafetoprotein levels triggered genetic analyses of SETX. We found the sib pair to be compound heterozygous
Introduction
■ Key words ataxia · ALS4 · ocular apraxia · peripheral neuropathy · dermatofibrosarcoma protuberans
bellar atrophy. Sensory-motor neuropathy is present in 93 % of patients [16, 20]. Increased alpha-fetoprotein (AFP) is a frequent serum marker of the disease but is neither specific nor obligatory [20]. Ocular apraxia is observed in AOA2 but also occurs in ataxia with ocular apraxia type 1 (AOA1) caused by APTX mutations, ataxia telangiectasia (AT) with ATM mutations and ataxia-telangiectasia-like disorder (ATLD) with mutations in MRE11 [9, 11, 17, 21, 30]. AOA2 (OMIM 606002) is allelic to ALS4 (OMIM 602433), a juvenile onset form of amyotrophic lateral
JON 2707
Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive early onset cerebellar ataxia caused by mutations in the senataxin (SETX) gene [20]. AOA2 was named after a characteristic oculomotor disturbance with impaired initiation of saccades that necessitates head movements to shift gaze. First signs typically occur between 10–25 years of age with progressive gait instability and impaired dexterity due to pronounced cere-
for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, resulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseudodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mutations were detected. Clinically this family presented with a phenotype combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations.
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sclerosis, also known as distal hereditary motor neuronopathy with pyramidal features [5]. Patients develop slowly progressive limb weakness with severe muscle wasting and pyramidal signs due to degeneration of upper and lower motor neurons. Bulbar and respiratory muscles are typically spared and overt sensory deficits are missing [4, 8]. In contrast to AOA2, ALS4 shows an autosomal dominant inheritance of SETX mutations. Here we describe an AOA2 family presenting with early onset ataxia and extensive muscle wasting due to severe sensory-motor neuropathy in two generations.
Patients and methods Two sibs with early onset ataxia were followed in the ataxia outpatient clinics at the Universities of Bochum and Essen since 1989. Neither of their parents had ataxia suggesting autosomal recessive inheritance, yet the paternal uncle turned out to be similarly affected. Therefore, the presumed mode of inheritance was questioned. Distant consanguinity in the paternal branch of the pedigree was not reported before genetic diagnosis was fixed (Fig. 1). Friedreich’s ataxia, as the most common recessive form of ataxia in Europe, and spinocerebellar ataxia type 1, type 2, type 3, type 6 and type 7, as the major mutations causing dominant ataxia, have been ruled out by genetic tests. All patients gave informed consent for molecular genetic analyses.
■ Analysis of the SETX gene Genomic DNA was extracted from peripheral venous blood samples by conventional methods. The primers used for PCR amplification of the exons of SETX were designed based on its DNA sequence (accession number NM_015046.5). Direct sequencing of the PCR products was performed using the automated fluorescence-based dideoxynucleotide termination method (MegaBACE 1000, Amersham Biosciences, Freiburg, Germany). ■ RT-PCR analyses Total RNA extraction was performed from 1.5 ml whole blood using the Invisorb Spin Blood RNA Mini Kit (Invitek) according to the manufacturer’s instructions. RT-PCR was performed by using a Qiagen One Step RT-PCR Kit and a primer set spanning the junctions of exons 13/14 and 16/17 (5’-TACAACATCTGAGAGAATTATTGCGTAC-3’, 5’-ACTCTTTTTTCATTCTGTGGTTTACTTG-3’). The reaction mixture was reverse transcribed (30 min at 50 °C and 15 min at 94 °C) and amplified for 30 cycles (1 min at 94 °C, 1 min at 58 °C and 1 min at 72 °C). The RT-PCR product was analyzed by 2 % agarose gel electrophoresis and ethidium bromide staining.
Results ■ Case reports VII-3 The 45 year old male noted an unsteady gait at 17 years of age. He used a walking stick at age 23, a stroller at 28, and
Fig.1 Pedigree of the AOA2 family with distal consanguinity. Squares represent males and circles females. Black symbols indicate affected and white symbols healthy individuals. Deceased family members are marked by a slash. Genotypes for the c.2835delC and the c.6106 G > A mutations are indicated. Pedigree structure is modestly modified for privacy reasons
I
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at age 31 he became dependent on a wheelchair. He was operated on strabismus at age 31, but double vision returned a few months after surgery. On examination, at age 35, his eyes were in a convergent position with some vertical skew.He had horizontal and vertical gaze evoked nystagmus, broken pursuit and dysmetric saccades but no signs of ocular apraxia.There were no swallowing difficulties despite reduced raising of the soft palate on phonation and an absent gag reflex. Dysarthria was marked and of cerebellar type.Walking was possible only for a few steps with significant support. Gait was broad based with severe foot drop and instability of the ankle, requiring orthopedic boots, because of severe atrophy and paresis of foot and lower leg muscles. The finger-tonose test was markedly ataxic and dysmetric with additional impairment of fine motor skills due to severe wasting and weakness of intrinsic hand muscles making it difficult to hold a pencil.Muscle stretch reflexes were lost and plantar response was normal. Sensory deficits were severe with pallanaesthesia,impaired position sense and graphaesthesia in the lower legs but only mild pallhypaesthesia in the upper extremities. International cooperative ataxia rating scale,at age 42,yielded a sum score of 72/100 [29]. At age 41, he developed skin cancer at the interscapular region with the histological diagnosis of dermatofibrosarcoma protuberans which required extensive surgery including resection of parts of the spinal muscles. MRI showed marked cerebellar atrophy (Fig. 2). Nerve conduction studies revealed severe sensory and motor neuropathy predominantly of axonal type. Sensory evoked potentials were missing at peripheral (Erb, L1) and central recording points. Amplitudes of visual evoked potentials were mildly reduced. Laboratory tests revealed increased AFP (108 ng/ml, normal: < 8.5) and creatin kinase levels (122 U, normal: < 70).
VII-4 The clinical picture of this 42 year old woman resembled much that of her older brother (VII-3). Gait ataxia started at age 14, a stroller was required at age 21 and she became wheelchair bound at age 32. She used prism glasses to compensate for mild diplopia. There were neither a clear axis deviation nor ocular apraxia but horizontal gaze evoked nystagmus. At 31 years of age ataxia of gait, stance and limbs was severe. Gait was additionally impaired by atrophy and paresis of lower limb muscles (e.g. foot dorsiflexion MRC 2/5). Intrinsic hand muscles were atrophic, too. There was severe proprioceptive impairment with pallanaesthsia of the lower limbs and reduced kinaesthesia. Muscle stretch reflexes were missing. Plantar response was normal. At age 42, she scored 50/100 on the international co-operative ataxia rating scale [29]. Nerve conduction studies revealed severe sensory and motor neuropathy of axonal type. Creatine kinase was within normal limits, but AFP was raised to 80.6 ng/ml (normal: < 8.5).
VI-1 The father of the index patients developed Parkinson’s disease at the age of 67 with classical features of rigidity, akinesia, rest tremor, positive levodopa response and mild drug induced psychosis after several years of dopaminergic treatment. There was no ataxia but reduced pallaesthesia of lower limbs and mild atrophy of small foot muscles. Stretch reflexes were preserved and plantar response was normal. Additionally, he suffered from pigmentary retinopathy and pronounced hearing difficulties ascribed to Meniere’s disease. Nerve conduction studies revealed mild to moderate sensory and motor neuropathy with axonal and de-
Fig.2 Magnetic resonance imaging of the brain of individual VII-3. T1 weighted sagittal (A), T2 weighted axial (B) and coronary FLAIR images (C) show severe cerebellar atrophy with sparing of the brainstem
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myelinating characteristics. He died at 75 years of age from ileus.
VI-2 The mother of the index patients did not show neurological abnormalities until the age of 73 but developed a carcinoma of the thyroid gland at age 60.
VI-3 The paternal uncle of the index patients suffered from gait ataxia since age 23. He used walking sticks since he was 30 years of age and became wheelchair dependent at age 39.At age 68, he presented with horizontal and vertical gaze evoked nystagmus and cerebellar dysarthria. He was severely ataxic and no longer able to sit without fixation. He developed severe intention tremor. Peripheral neuropathy was evident with wasting of leg and hand muscles, areflexia and impaired sensation for vibration, kinaesthesia, pinprick and temperature discrimination. He died in a completely dependent state at the age of 75.
■ Genetic analyses Sequencing of the complete coding region of SETX revealed a single base deletion c.2835delC in exon 10 (p.D945EfsX8) and a base exchange c.6106G > A in exon 15. The index sib pair was compound heterozygous for both mutations. The deletion c.2835delC was inherited by the mother while the father carried the c.6106G > A mutation in heterozygous state. The uncle of the index patients, who also was affected by ataxia, was homozygous for the c.6106G > A mutation (Fig. 1). Fig.3 Analysis of the SETX gene and its mRNA in patient VII-3. A, B Genomic DNA sequencing revealed SETX mutations in heterozygous state. The wild type nucleotide sequence is shown above the electropherogram tracing. C Analysis of splicing products using RTPCR with primers (horizontal arrows) amplifying the shaded fragment in the depicted SETX gene section. The c.6106G > A mutation is indicated by vertical arrow. D RT-PCR products from patient VII-3 and a control as analyzed on an ethidium bromide-stained agarose gel. Exonic primers amplifying exons 14–16 of SETX cDNA showed the presence of the expected 455bp transcript in the control lane 1. This fragment was hardly detectable in patient VII-3 (lane 2), whereas an additional smaller fragment is observed, apparently 298bp in length, thus obviously lacking exon 15 (pUC Mix Marker in lane M)
Neither the deletion of cytosine in position 2835 nor the base exchange c.6106G > A were found in 350 control chromosomes from healthy probands. Since the substitution (6106G > A) is located in the last base of exon 15 of SETX and potentially alters the donor splice site of exon 15 critically, we investigated whether this mutation affects correct splicing of the SETX mRNA by RT-PCR analysis using primers that flanked exon 15. In a control subject, a fragment of the expected size (455bp) was amplified. In contrast, in patient VII-3 there was an additional, shortened fragment which size reflects the absence of exon 15 (Fig. 3). These findings indicate that the base exchange c.6106G > A resulted in abnormal splicing and skipping of exon 15. Furthermore, consistent with this type of mutation, we demonstrated that D945EfsX8 mRNA is degraded by nonsense mediated mRNA decay (NMD; see Fig. 3), since the normal fragment in patient VII-3 showed marked reduction in the relative levels of mRNA.
Discussion This family is exemplary for the difficulties in clinical differentiation of hereditary ataxias. The index patients were initially diagnosed as Friedreich’s ataxia (FA) because of early onset ataxia, areflexia, weakness, sensory loss, axonal neuropathy and dysarthria. Although absence of Babinski’s sign, presence of severe motor neuropathy, marked nystagmus, normal electrocardiogram and prominent cerebellar atrophy on MRI are unusual in FA, atypical phenotypes occur in up to 20 % of genetically proven FA [10, 12, 24]. After genetic testing for frataxin mutations became available, FA, as the most frequent type of autosomal recessive ataxia, was excluded
Ex 10: c.2835delC
c. 6106 G > A
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(19bp)
Ex14 (168bp)
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Ex16 (102bp)
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500bp 404bp 331bp 242bp
d b
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Ex17
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in our family [3]. After affection of the paternal uncle of the index sib pair was confirmed, autosomal dominant cerebellar ataxia was suspected, but the most frequent subtypes like SCA1, SCA2, SCA3, SCA6 and SCA7 were excluded as well [25]. Spinocerebellar ataxia type 4 (SCA4), which goes along with peripheral neuropathy, was considered but the gene had not yet been cloned [13]. Further ataxias associated with severe peripheral neuropathy, as a complicating feature, include autosomal recessively inherited AOA1 [19], AOA2 [20] and spinocerebellar ataxia with axonal neuropathy (SCAN) [27] as well as autosomal dominantly inherited SCA3 [14], SCA18 [2] and SCA25 [26]. In a repeated work-up, elevated AFP in our patients gave the clue to suspect AOA2 and to investigate the SETX gene. Despite its designation as AOA, ocular apraxia is not an obligatory feature of AOA2. It turned out to be present only in about 47 % of genetically proven AOA2 patients [7]. Although only few larger series have been reported, early onset of ataxia, marked cerebellar atrophy on MRI and elevated AFP levels are regarded as hallmarks of AOA2 [1, 7, 16, 20]. This family demonstrates substantial overlap of AOA2 and ALS4 features with pronounced distal weakness and wasting in hand and feet muscles. ALS4 frequently results in wheelchair-dependence and almost no functional hand use by the 5th or 6th decade of life while sparing bulbar and respiratory muscles as it was observed in the eldest affected (VI-3). In contrast to ALS4, sensory deficits were pronounced at least in the legs and pyramidal signs were missing in our family. Differential phenotypical expression of SETX mutations, like ALS4 or AOA2, have been ascribed to potentially different mutational effects.ALS4 is supposed to be caused by a dominant acting toxic gain of function whereas the recessive loss of SETX function causes AOA2 [5]. The family presented here fits this theory since the single base deletion c.2835delC causes nonsense mediated mRNA decay and the base exchange c.6106G > A results in abnormal splicing and skipping of exon 15. In murine brain, SETX shows high expression in neurons of the cerebellum, hippocampus and olfactory bulb. Beside diffuse cytoplasmic expression, it is found in the nucleolus and also within the nucleoplasm in a cell-cycle dependent manner [6]. Whereas about half of nucleolar proteins are related to ribosome biogenesis, other functions of nucleolar proteins include control of
aging and modulating telomerase activity. Although the function of SETX is still unknown, it contains a DNA/RNA helicase domain suggesting a role in RNA processing and DNA repair [28]. Whether defective DNA repair mechanisms in AOA2 increase risk of cancer as in ataxia telangiectasia is not established [15, 22]. Yet, the association of the rare type of ataxia (AOA2) and the uncommon skin cancer (dermatofibrosarcoma protuberans) in the index patient VII-3 might add to this hypothesis. Dermatofibrosarcoma protuberans arises from the rearrangement of chromosome 17 and 22 such that the collagen type Iα1 gene (COLIA1) becomes fused to the platelet-derived growth factor β-chain gene (PDGFB). This rearrangement leads to continuous activation of the PDGF receptor β protein tyrosine kinase which promotes dermatofibrosarcoma protuberans cell growth [18]. On this background, it is interesting to note that over-expression of SETX is associated with splenic marginal zone lymphoma [23], which supports the hypothesis that dysregulation of SETX may be involved in malignant transformation. The observation of Parkinson’s syndrome, pigmentary macula degeneration, hearing loss and peripheral neuropathy in the father (VI-1) raises speculation that one or more of these problems are due to the heterozygous c.2835delC mutation in SETX.Clinically,no signs of neurological disease have been observed in the other mutation carriers (VI-5, VII-2 and VII-5) with the restriction that all were younger than individual VI-1 and were not available for electrophysiological examination. Prospective analysis of larger numbers of elderly mutation carriers may clarify whether AOA2 haploinsufficiency is related to neurodegenerative symptoms that do not fall into the clinical spectrum of AOA2. In this study, we found a sib pair to be compound heterozygous for a single base deletion c.2835delC resulting in a frameshift mutation causing nonsense related mRNA decay and a base exchange c.6106G > A resulting in abnormal splicing and skipping of exon 15. Whereas missense mutations cluster in the N-terminal putative protein interaction domain and the C-terminal helical domain, nonsense mutations show no mutational hot spots but scatter all over the gene and require sequencing of the whole coding region for diagnostic purposes [6]. This family is the first example of “pseudodominant” inheritance in AOA2 most likely due to distant consanguinity in the paternal branch of the family.
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