Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent ...

Neurogenetics (2011) 12:193–201 DOI 10.1007/s10048-011-0281-x

ORIGINAL ARTICLE

Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients Barbara Castellotti & Caterina Mariotti & Marco Rimoldi & Roberto Fancellu & Massimo Plumari & Sara Caimi & Graziella Uziel & Nardo Nardocci & Isabella Moroni & Giovanna Zorzi & Davide Pareyson & Daniela Di Bella & Stefano Di Donato & Franco Taroni & Cinzia Gellera

Received: 2 September 2010 / Accepted: 9 March 2011 / Published online: 5 April 2011 # Springer-Verlag 2011

Abstract Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The B. Castellotti : C. Mariotti (*) : M. Rimoldi : R. Fancellu : M. Plumari : S. Caimi : D. Di Bella : S. Di Donato : F. Taroni : C. Gellera SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy e-mail: [email protected] G. Uziel : N. Nardocci : I. Moroni : G. Zorzi Child Neurology Department, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy D. Pareyson SOSD Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy

clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition. Keywords Aprataxin . APTX . Oculomotor apraxia . Recessive ataxia

Introduction Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of hereditary neurodegenerative diseases characterized by degeneration of cerebellum often associated with peripheral nervous system involvement, ophthalmologic disturbances, and systemic abnormalities [10, 33]. In recent years, a subgroup of recessive ataxias associated with oculomotor apraxia (OMA) has been clinically and genetically characterized [13, 19, 32]. OMA has been originally defined as an impaired ability to generate saccades on command [4]. In ataxia with OMA, the oculomotor disturbance is rather characterized by the inability to coordinate eyes/head movements to reach a lateral target, since the head turns and reaches the target before the eyes [21]. At present, the group of ataxias with OMA includes four distinct entities: ataxia-telangectasia (AT), AT-like disorder (ATLD), ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2 (AOA2). AOA 1 (MIM 208920) was initially described in Japanese patients as a new clinical entity characterized by

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early-onset cerebellar ataxia, mental retardation, hypoalbuminemia (EAOH), hypercholesterolemia, and neuropathy [11, 17, 18]. A similar phenotype, except for the absence of mental retardation, was observed in several Portuguese families [2]. Linkage to the same region on chromosome 9p13.3 [23] and the mutations in a new gene (APTX) were found both in Japanese and Portuguese families [7, 23, 24]. The APTX gene encodes for a nuclear histidine triad (HIT) protein, named aprataxin, involved in DNA single-strand break repair [24, 29]. Although many HIT proteins had been identified, aprataxin was the first to be linked to a distinct neurological phenotype. In vitro studies demonstrated that aprataxin is involved in DNA repair processes, interacting with several polypeptides, including X-ray repair crosscomplementing 1 and poly-ADP ribose polymerase 1 [15], which are crucial components of the DNA single- and double-strand break repair complexes [3]. However, the pathological mechanism leading to neurodegeneration, as observed in AOA1 disease, is still unknown. The clinical phenotype of AOA1 is characterized by an early-onset cerebellar syndrome, nystagmus, dysarthria, peripheral axonal neuropathy, muscle weakness, and distal loss of position and vibration sense. Cerebellar atrophy is present in all cases, while hematological findings, such as hypoalbuminemia and hypercholesterolemia, become evident during late disease stages. Mental retardation is described, with different percentages, in several series of patients, and OMA can be present only at the onset or be absent at all. Other variable features, include mild to severe dystonia [21, 30], intentional tremor [14, 35], and choreoatetosis movements [5, 6, 9, 14, 21, 35]. Recently, reduced levels of muscle coenzyme Q10 (CoQ10) have been observed in a few patients with AOA1 [20, 28], suggesting the possibility of a beneficial effect of CoQ10 supplementation. Here, we describe clinical, biochemical, and molecular features of a large cohort of Italian AOA1 patients. The aims of the study were to: (1) detect novel and recurrent mutations by sequence analysis of all seven exons of the APTX gene, (2) describe the neurological phenotype associated with APTX mutations, (3) extend the biochemical analyses of CoQ10 levels in muscle biopsies, cultured fibroblasts, and plasma from of APTX mutated patients, and (4) determine and compare the relative frequency of APTX mutations in patients with progressive ataxia and in patients with early-onset undiagnosed chorea.

Neurogenetics (2011) 12:193–201

sporadic presentation (n=181) or with family history compatible with autosomal recessive inheritance (n=23). In all cases, molecular investigation excluded the presence of the GAA triplet expansion associated with Friedreich ataxia. Patients with APTX gene mutations underwent neurological examination, brain MRI, motor and sensory nerve conduction studies, and biochemical determinations of total cholesterol, albumin, and alpha-fetoprotein (AFT). For the analysis of coenzyme Q10 levels, skin biopsy and needle muscle biopsy of the left quadriceps were performed in six patients. In addition, we screened for APTX mutations a group of 52 Italian patients presenting with early-onset (A transversion at nt 742 resulting in the amino acid substitution leucine–methionine (p.L248M, exon 5), and a T>G transversion at nt 555, resulting in an aspartic to glutamic acid substitution (p.D185E, exon 5). In all cases, sequence analysis of the entire coding sequence and realtime PCR analyses failed to identify other APTX mutations or deletions in these patients. The p.D185E variant was found only in one sporadic case. The p.L248M variant was identified in four sporadic cases and in a family with two affected siblings. In this family, the variant was found in the two affected brothers and in their healthy mother. The same

F 6 32 Y-31 ++ + ++ Y ++ Abs N ++ ++ + N +++

M 6 22 N ++ + +

Y N Abs N ++ ++ N + ++

Sex Age at onset Age at exam Chair bound—years Gait–limb ataxia Dysarthria Defects of saccadic initiation Nystagmus Choreoathetosis DTR lower limbs Babinski sign Distal weakness UL Distal weakness LL Muscular wasting Cognitive impairment Decreased vibration sense LL Y + Abs N + + + N N

M 6 32 Y-22 ++ ++ N

2 W279X W279X 6

3 P977

Y na Abs N ++ ++ ++ MR na

F 5 30 Y-29 +++ + na

3 W279X W279X 6

4 A301

Y + Abs Y + ++ ++ MR +++

F 7 26 Y-23 ++ + ++

3 W279X W279X 6

5 P980

Y +++ Abs N + + ++ MR na

M 6 9 N ++ +++ ++

4 W279X W279X 6

6 P1054

na ++ Abs N N N N N na

M 4 13 N + ++ ++

5 W279X W279X 6

7 A1414

Y N Abs Y + + + + +

F 5 29 N ++ + ++

6 W279X W279X 6

8 P1619

na N Abs N N + N MR na

M 3 12 N ++ + +

7 W279X W279X 6

9 P1555

Y ++ Abs Y + + + + +

M 7 28 N +++ ++ ++

8 R306X R306X 6

10 P1657

na na Abs na na na na MR na

9 W279X R306X 6 7 M 6 24 N ++ + na

11 P527

Y + Abs N + +++ ++ + +

10 W279R Q181X 6 4 M 3 27 Y-23 +++ +++ +++

12 A1015

Y yes, N no, + mild, ++ moderate, +++ severe, na not available, DTR deep tendon reflexes, Abs absent, LL lower limbs, UP upper limbs, MR mental retardation

Data in bold are novel APTX mutations

APTX exons

1 W279X W279X 6

1 W279X W279X 6

Family N. APTX mutation (protein, amino acid residues)

2 P1028

1 P1027

Patient code

Table 1 Clinical and genetic characteristics of AOA1 patients

Y na Abs na na na + N ++

11 W279R I159fs 6 3 M 7 30 N ++ ++ ++

13 P645

Y + Abs N +++ +++ +++ ++ na

M 6 55 Y-20y +++ + ++

12 W279R W279R 6

14 P1037

na + Abs N N N N MR +

M 6 16 N ++ + ++

13 P206L P206L 5

15 A1218

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Novel APTX mutations 477delC

K160fs Exon 3

W279X/480delC

Gln CAG>TAG Stop

Q181X Exon 4

W279X/Q181X

Arg CGA>TGA Stop

R306X Exon 7

W279X/R306X

Fig. 1 Automated direct sequence analysis of APTX gene and the pedigrees of the patients carrying novel APTX mutations. Arrows indicate the mutated nucleotide. In all cases, the new mutations were found in compound heterozygous subjects, harboring the recurrent p. W279X mutation on the other allele. Left the deletion of a C residue at

nucleotide position c.477 causes a frame-shift in the reading frame (p. I159fsX171); center, a C-to-T transition at nt c.541 results in the nonsense p.Q181X mutation in exon 4; right, a C-to-T transition at nucleotide c.916 causes the nonsense p.R306X mutation

variant was also present in the unaffected mother of a sporadic patient. No DNA samples from other unaffected relatives were available for molecular investigation. Both the p.L248M and p.D185E variants were not found in 752 control chromosomes. RNA analysis for the p.L248M variant did not show alternative splicing products. WB analysis of three of five patients carrying the L248M heterozygous missense variant demonstrated an amount of aprataxin protein comparable to controls. (Fig 2) The six subjects, from five families, carrying the heterozygous variant p.L248M had an age at onset ranging from 1 to 16 years and presented a progressive ataxic syndrome with cerebellar atrophy at MRI. None had sensory–motor neuropathy; two of five had mental retardation and epilepsy. The subject heterozygous for the p.D185E variant presented visual impairment and maculopathy at the age of 18, associated with progressive gait and limb ataxia, cognitive impairment, and epilepsy. All these patients had normal levels of albumin, cholesterol, and alpha-fetoprotein.

cases harbored the p.W279X nonsense mutation, previously found in several AOA1 patients of European origin suggesting the possibility of a founder effect in these populations [14, 21, 24] (Fig. 3) Two other patients carried known missense mutations: the p.P206L, previously found in most Japanese patients and in an Italian case [7, 24], and the p. W279R mutation, already identified in a French patient [21] (Fig. 3.). Four patients of the present study harbored novel APTX mutations, all causing a truncation of the protein. Both truncating and missense mutations have already been described in AOA1 patients. As expected for recessive disorder, a loss-of-function mechanism has been hypothesized. The long aprataxin isoform contains three functional domains: an N-terminal domain of polynucleotide kinase3′-phosphatase (PNKP), called PNKP–aprataxin amino-terminal domain (PANT), a central HIT domain, and a C-terminal DNA-binding zinc finger (ZF) domain [15]. The large majority of the disease-causing mutations, identified so far, are truncating mutations localized in exons 5, 6, and 7 and affect the HIT hydrolase domain [1, 14, 21, 30, 34] (Fig. 3). Two of the novel APTX mutations described in this study cause an early truncation of the protein: the p.I159fsX171 mutation, is one of the few APTX mutations located in exon 3 and affecting the PANT domain, while the p.Q181X is the only mutation described in exon 4 and causes the deletion of the HIT and of the C-terminal domains. Both mutations were found in subjects heterozygous for the p.W279X mutation. WB analysis showed that the levels of the mutated proteins in lymphocytes from the patients were almost undetectable,

Discussion AOA1 is the most common autosomal recessive ataxia in Japan and the second most common form, after Friedreich ataxia, in Portugal [7, 24]. In our survey, AOA1 account for approximately 6% of the non-Friedreich cases with sporadic or autosomal recessive cerebellar ataxia. This figure is similar to that found in France (5.7%) [21] and Portugal [2, 23, 24]. The majority of our

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Table 2 Summarized clinical, biochemical, and radiological findings in AOA1 patients

Families, N Consanguinity Age of onseta Age at examinationa Age at chair bounda Clinical features Gait–limb ataxia Dysarthria Difficulty in saccadic initiation Nystagmus Choreic movements Absent DTR in lower limbs Babinski sign Distal limb muscle weakness Limb muscle wasting Decreased vibration sense LL Cognitive impairment Biochemical findings Hypoalbuminemia Hypercholesterolemia Increased CK Normal alpha-fetoprotein Electrophysiological findings Peripheral neuropathy Brain MRI Atrophy of cerebellar hemispheres and vermis

APTX mutated patients (N=15) 13 5/13 5.4±1.35 (3–7) 25.7±11.1 (9–55) 24.7±4.3 (20–31) 15/15 15/15 12/13 11/11 9/12 15/15 3/13 11/13 10/14 8/9 11/15

100% 100% 92% 100% 75% 100% 23% 85% 71% 89% 73%

7/12 9/13 3/7 8/11

58% 69% 43% 73%

13/13

100%

14/14

100%

DTR deep tendon reflexes, CK creatine kinase a

Mean of years, (range)

confirming the hypothesis of a loss-of-function pathogenic mechanism (Fig. 2). Similar results were previously obtained in tissues and cells derived from patients homozygous for the truncating p.W279X mutation [3, 31]. In the present study, we also detected a novel homozygous stop mutation in exon 7, p.R306X, causing the loss of the last 36 last amino acids residues of the protein. This mutation, as the common p.W279X mutation, causes the deletion the ZF domain and leaves the HIT domain intact [15]. WB analysis indicated that the levels of expression of the mutated protein in lymphocytes from the patient were greatly decreased (Fig. 2), as previously observed in patients carrying other truncating and missense diseaseassociated mutations [9, 13, 25], probably due to instability of the mutated protein [16]. In addition, molecular screening allowed the identification of two heterozygous APTX sequence variants: p. L248M and p.D185E. In both cases, mRNA analysis and real-time PCR excluded the presence of a second splice-site mutation or deletion, and WB demonstrated a normal amount of the aprataxin protein. DNA analysis of the parents from two unrelated families demonstrated the presence of the p.L248M APTX variant in the healthy mothers. In the cohort of subject with isolated choreic disorders, we found neither APTX mutations nor variants. We confirmed that chorea is noticed in the early stages of AOA1 disease in a large percentage of cases [21]; however, this feature is almost invariably associated with cerebellar ataxia. Clinical presentation was homogeneous in all our patients, irrespectively of the type and location of the APTX mutation. We did not observed patients with lateonset disease, as described by Criscuolo [5], and even the patients, harboring the missense p.P206L and p.W279R

Table 3 Coenzyme Q10 levels in muscle tissue, cultured fibroblasts, and plasma of AOA1 patients AOA1 patients Patient code P1027 P1028 P980 P1619 A1015 P1657 AOA1 patients Mean±SD Range Controls Mean±SD Range

APTX mutations p.W279X/p.W279X p.W279X/p.W279X p.W279X/p.W279X p.W279X/p.W279X p.W279X/p.Q181X p.R306X/p.R306X

Muscle CoQ10 (pg/mg of protein)

Fibroblasts CoQ10 (ng/mg of protein)

Plasma CoQ10 (μmol/L)

100 59 151 162 172 104

66 61 55 50 70 66

1.99 1.79 – – 1.69 1.04

124.7±44 59–172

61.33±7.58 50–70 (n=11) 83.54±25.2 56–123

1.9±0.5 1.0–2.0 (n=5) 1.17±0.34 0.9–1.7

142.2±37 89–194


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Fig. 2 Western blot analysis of wild-type and mutated aprataxin proteins (upper). Aprataxin levels were normalized against a control protein (MCAD; lower). Patients carrying APTX mutations on both alleles (lanes 3–7) show undetectable amount of the mutated aprataxin

protein, as compared with wild-type normal controls (lanes 1–2). Patients carrying the APTX sequence variant p.L248M in heterozygous form (lanes 8–10) had levels of expression of aprataxin comparable to controls

mutations, did not differ from other patients with respect to onset and clinical features [5, 7]. We found slightly raised AFT in three cases. This is an infrequent finding in AOA1 patients (Table 2), since it has been described only in a 10-year-old Lebanese girl carrying the homozygous p.A198V mutation [6]. Hypoalbuminemia and hypercholesterolemia are the most characteristic biochemical findings in AOA1 patients, whereas increased of AFT is typical of patients with AT or AOA2 [26]. AOA1 patients were shown to have normal protein intake and normal rate of albumin degradation, thus a decreased synthesis of albumin in liver was suspected, and secondary hypercholesterolemia was hypothesized [11]. Interestingly, in postnatal terminally differentiated hepatocytes, AFT is repressed and albumin expression initiates [26]. Thus, in a subgroup of AOA1 patients, increased AFT and decreased albumin, in the absence of liver diseases, could be signs of hepatocyte dedifferentiation. However, the mechanism and the possible role of mutated aprataxin on these hepatic features remain to be explained. To complete the analysis of AOA1 phenotype, we also performed analysis of coenzyme Q10 (CoQ10) levels in

muscle, fibroblasts, and serum from a subgroup of patients. In the present study, we did not confirm previous results suggesting the association of the disease with reduced level of CoQ10 in muscle tissue [6, 20, 27]. Up to now, CoQ10 muscle levels were measured in ten AOA1 patients, and reduced CoQ10 levels were reported in nine: six patients were homozygous for the p.W279X mutation [20, 27], one subject carried p.W279X and p.D267G mutations [20], and two subjects were homozygous for p.A198V missense mutation [6, 20]. In these patients, the ages at examination ranged from 10 to 38 years, and no correlation with CoQ10 deficiency was found for disease duration, severity of symptoms, or rate of disease progression [6, 20, 27]. In our study, only one subject, carrying the recurrent p. W279X mutation, had a partial CoQ10 defect in muscle (42% of mean control value) while the other five subjects had normal CoQ10 values (Table 3). Ages at examination, disease durations, and type of APTX mutations were similar in our and in previously investigated cases, and did not significantly differ between the group of patients with reduced CoQ10 levels in comparison with the patients with normal values (Tables 1 and 3) [6, 20, 27].

APTX gene mutations 60

N. of mutated chromosomes

Fig. 3 Graph showing APTX mutations identified in patients from different countries, including the novel mutations found in the Italian AOA1 patients of the present study (in bold)

50 40 30

Italy Tunisia Pakistan Australia Israel Lebanon Portugal Germany France Japan Ireland

20 10 0

Exon Exon 3 4

Exon 5

Exon 6

Exon 7

200

Muscle CoQ10 findings in AOA1 patients remain controversial; however, our data seem to indicate that reduced CoQ10 muscle content is not a consistent finding in this disease, and it may likely represent a secondary event unrelated to specific clinical or molecular features [8]. The normal CoQ10 levels detected in cultured fibroblasts and plasma from the same patient with decreased muscle CoQ10 may also support this hypothesis. In conclusion, our study indicates that APTX mutations are responsible of approximately 6% of early-onset cerebellar ataxia in a large cohort of Italian patients. The identification of APTX mutation in exons 3 and 4 indicates that a complete mutational screening should be performed in order to detect all possible mutations and reach the correct prevalence of the disease in the study population. In fact, mutations in these two exons might have been missed in previous studies, in which only partial screening of exons 5, 6, and 7 was performed [21]. Our results also indicate that APTX genetic screening should not be considered for patients with isolated choreic disorders. Decreased levels of CoQ10 in muscle tissue may be occasionally associated with the disease, but this biochemical feature does not represent a reliable tool for clinical screening. In our large series of AOA1 patients, we observed a homogenous clinical phenotype characterizing this rare neurological condition. Acknowledgments The authors are grateful to Mrs. Simona Allievi for cell culture and biochemical analyses and to Dr. Floriano Girotti for referring a patient. Study partially supported by Italian Minister of Health (R.C. 2008–2009).

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