Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management

Abstract

While Friedreich's ataxia (FRDA) and ataxia telangiectasia (AT) are known to be the two most frequent forms of autosomal recessive cerebellar ataxia (ARCA), knowledge on the other forms of ARCA has been obtained only recently, and they appear to be rarer. Little is known about the epidemiological features and the relative frequency of the ARCAs and only few data are available about the comparative features of ARCAs. We prospectively studied 102 suspected ARCA cases from Eastern France (including 95 from the Alsace region) between 2002 and 2008. The diagnostic procedure was based on a sequential strategic scheme. We examined the clinical, paraclinical and molecular features of the large cohort of patients and compared features and epidemiology according to molecular diagnosis. A molecular diagnosis could be established for 57 patients; 36 were affected with FRDA, seven with ataxia plus oculomotor apraxia type 2 (AOA2), four with AT, three with ataxia plus oculomotor apraxia type 1 (AOA1), three with Marinesco-Sjögren syndrome, two with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), one with ataxia with vitamin E deficiency (AVED) and one with autosomal recessive cerebellar ataxia type 2 (ARCA2). The group of patients with no identified mutation had a significantly lower spinocerebellar degeneration functional score corrected for disease duration (SDFS/DD ratio; p = 0.002) and comprised a significantly higher proportion of cases with onset after 20 years (p < 0.01). Extensor plantar reflexes were rarer and cerebellar atrophy was more frequent in the group of patients with a known non-Friedreich ARCA compared to all other patients (p < 0.0001 and p = 0.0003, respectively). Lower limb areflexia and electroneuromyographic evidences of peripheral neuropathy were more frequent in the Friedreich ataxia group than in the group with a known non-Friedreich ataxia and were more frequent in the later group than in the group with no identified mutation (p = 0.0001 and p = 0.01, respectively). The overall prevalence of ARCA in Alsace is 1/19,000. We can infer the prevalence of FRDA in Alsace to be 1/50,000 and infer that AT is approximately eight times less frequent than FRDA. MSS, AOA2 and ARSACS appear only slightly less frequent than AT. Despite the broad variability of severity, Friedreich ataxia patients are clinically distinct from the other forms of ARCA. Patients with no identified mutation have more often a pure cerebellar degenerative disease or a spastic ataxia phenotype. It appears that ARCA cases can be divided into two major groups of different prognosis, an early-onset group with a highly probable genetic cause and an adult-onset group with better prognosis for which a genetic cause is more difficult to prove but not excluded. ARCAs are rare, early-disabling and genetically heterogeneous diseases dominated by FRDA. Several of the recently identified ARCAs, such as AVED, ARSACS, AOA1, AOA2 and MSS, have a prevalence close to AT and should be searched for extensively irrespective of ethnic orig...

Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…4,5 Neuroimaging findings include slowly progressive atrophy of the superior vermis, and atrophy of the cerebellar hemispheres, cervical spinal cord, and cerebral cortex. 5,6 The description of characteristic bilateral, parallel, paramedian, T2 hypointense stripes on MR imaging contributed to an increased diagnosis of ARSACS. 7 By measuring anisotropic diffusion of water in the WM, DTI detects abnormalities in the myelin, axon, or orientation of fibers within the bundle.…”

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects

“…Recently, MRI of five patients in Quebec revealed linear hypointensity in T2-and Fluid-Attenuated Inversion Recovery (FLAIR) images of the pons (Martin et al, 2007). Thereafter, the same findings have been reported in only one patient in each of the Netherlands (Van Damme et al, 2009), France (Anheim et al, 2010), and Italy (Terracciano et al, 2010).…”

Inherited Cerebellar Ataxia in Childhood: A Pattern-Recognition Approach Using Brain MRI

“…According to the literature, the most common causes of CAC with cerebellar atrophy are Friedrich ataxia, ataxia with oculomotor apraxia types 1 and 2, ataxia telangiectasia, and infantile-onset spinocerebellar ataxia. 3,4,9,12,14 Clinical clues for a conclusive diagnosis can be found from history, physical examination (in ataxia telangiectasia), and laboratory examinations, but imaging is usually requested as a complementary test.…”

“…The absolute prevalence of inherited CAC is not known, though it has been estimated to be 5.3 per 100,000 inhabitants in some regions. 12 Although few causes of inherited CAC can be treated, a specific diagnosis is important for accurate genetic counseling because many of the disorders are inherited as AR traits and the risk of having an affected child in future pregnancies is 25%. In addition, new drugs and gene and stem cell therapies are being developed and will require a better understanding and a confident diagnosis of the underlying disease.…”

“…Because the absolute prevalence of most disorders with CAC is not known, we list the most prevalent diseases based on literature data and the authors' experience. [12][13][14] It is beyond the scope of this article to review all potential causes of childhood ataxia. Our goal is to emphasize MR imaging patterns, clinical findings, and confirmatory tests that the well-informed neuroradiologist can suggest, thus playing an important role in the early management of affected patients.…”