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Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are clinically and genetically heterogeneous. Seven types of EA have been reported so far but the majority of clinical cases result from two recognized entities.Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia and dysarthria, and interictal myokymia. Onset occurs during the first two decades of life. Associated epilepsy has been reported in some EA1 patients. EA1 is caused by mutations of the KCNA1 gene coding for the voltage-gated potassium channel Kv1.1. Mutation is mostly missense mutations. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Episodic ataxia type 2 (EA2) is characterized by episodes lasting longer than in EA1, that manifest by ataxia, dysarthria, vertigo, and also, in most of the cases, an interictal nystagmus. Other clinical features as developmental delay or epilepsy can be present in some patients. Brain MRI shows frequently a vermian atrophy. Onset occurs typically in childhood or early adolescence, but can sometimes be in adulthood. EA2 is caused by mutations in CACNA1A, a gene coding for the neuronal voltage-gated calcium channel Cav1.1. For two-thirds of the cases, mutations lead to a stop codon. This type is most often responsive to acetazolamide that reduces the frequency and severity of attacks, but does not appear to prevent the progression of interictal symptoms.This article summarizes current knowledge on episodic ataxia type 1 and 2 and describes briefly the other types of EA.Molecular analysis of KCNA1 or CACNA1A provides a confirmation of the diagnosis of EA1 and EA2. Other types remain rare phenotypic variants. Among them, only two genes have been identified: CACNB4 in EA5 and SLC1A3 in EA6 and mutations have been found in a very few cases. No mutation can be detected in some familial cases of episodic ataxia, suggesting further heterogeneity.

Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous and complex inherited neurodegenerative diseases that may affect the cerebellum and/or the spinocerebellar tract, the posterior column of the spinal cord and the peripheral nerves. Cerebellar ataxia is frequently proeminent and mostly associated with several neurological or extra-neurological signs, leading to a major disability before the age of 30.Friedreich's ataxia (FRDA) is clearly the most frequent ARCA and several rarer entities have been described during the past fifteen years such as ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2), ataxia with vitamin E deficiency (AVED) and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ACAR are characterized by both allelic and non-allelic genetic heterogeneity. They may be divided into three groups: spino-cerebellar ataxia with pure sensory neuropathy; cerebellar ataxia with sensori-motor axonal neuropathy; pure cerebellar ataxia (i.e. ataxia of purely cerebellar origin that may be associated with other symptoms). Common physiological pathways are involved in several ARCA, such as DNA repair deficiency (AOA1, ataxia telangiectasia [AT]…), RNA termination disorder (AOA2), mitochondrial defect (FRDA, sensory ataxic neuropathy with dysarthria and ophthalmoplegia [Sando]…), lipoprotein assembly defects (AVED, abetalipoproteinemia [ABL]), chaperon protein disorders (ARSACS, Marinesco-Sjögren syndrome [MSS]) or peroxysomal diseases (Refsum disease [RD]).New nanotechnology methods and high throughput gene analysis as well as bioinformatics should lead to the identification of several new ARCAs in the next few years despite the rarity of these entities. However, the challenge of the next decades will be the discovery of efficient treatments for these disabling neurodegenerative disorders.Clinicians should be aware of the more frequent ARCAs, especially FRDA, in addition to ARCAs for which treatment is available (FRDA, AVED, ABL and RD for instance).

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

A 72-year-old man experienced increasing difficulties in calculating and processing numbers. He made many syntactic errors when he read and wrote numbers, both in arabic and number-word forms. Transcoding between arabic numerals and number-words was severely impaired. His calculation abilities were grossly impaired. He could not perform even simple multiplications, but additions and subtractions were preserved. He was unable to recite multiplication tables or the alphabet. In contrast, numerosity judgment, magnitude comparisons,and semantic evaluation of numbers were intact. The patient's deficit could be summarized as an Impairment in all tasks involving numbers in a verbal format, corresponding to the so-called "verbal anarithmetia'." It was noteworthy that verification of operations, including multiplications, was accurately performed. For example, the patient could not solve a multiplication like 8 x 9, but could estimate that 9 x 2=1 1 was closer to the exact result than 9 X 2=17, or could state that 8 x 2=16 was exact even though, at the same time, he expressed verbally the terms of the corresponding addition "eight plus two is ten." Other cognitive deficits were detected by neuropsychological tests which demonstrated mainly anomic aphasia, dysorthographic agraphia without alexia, impairment of short term and episodic memory, digital agnosia. However, the patient could not be considered to have demon-eti due to preserved self-sufficiency, except for tasks requiring calculation abilities. During the two years of follow-up, the impairment in processing numbers and calculation remained predominant over other deficits. Cerebral MRI showed an atrophy of the left temporal and parietal lobes, and SPECT study showed a reduction of regional cerebral blood flow of the left hemisphere. This original clinical presentation of a cerebral degenerative disease could be described as "primary progressive acalculia" whatever the underlying primary pathological process.

The developmental characteristics of the cerebellum, including its histogenesis which persists well beyond birth, explain, at least in part,why the mechanisms of cerebral disorders of infancy remain equivocal. The nosology of certain congenital ataxias, especially those with cerebellar hypoplasia, remains ambiguous, at the crossroads between early degenerative disease and congenital non-progressive anomalies. We have revisited the clinical approach to the most frequent situations: (1) the careful dysmorphology work-up must search for any element of various recognizable syndromes, especially those transmitted by autosomal recessive inheritance. An update of list of such syndromes is provided. (2) Cerebellum imaging must be obtained as early as possible and re-documented with a long-term follow-up. Emerging 3D techniques should help improve morphological evaluation. (3) One the contrary, a complex biochemical work-up, looking for metabolic diseases, is required only when the clinical and radiological evaluations provide unusual data. (4) Mental status is always the most relevant element of prognosis. t is frequently compromised, including in congenital non-progressive ataxia with normal imaging. Beyond the classical strategies, the genetic approach must take into consideration possible phenotypic homologies with natural or experimental animal models. This approach is illustrated by the recent discovery of mutations with the human homolog of the Reeler gene in a subset of cerebellar agenesis associated with other dysgenetic elements.

Historical review on hereditary spinocerebellar degenerations (SCD) revealed that some CAG repeat diseases were formerly diagnosed under several different names because of their clinical and pathological heterogeneity. A genetic abnormality in these hereditary SCDs (often with expanded CAG repeat) corresponds to a definite prototypic combination of the principal lesions in the cerebellar, extrapyramidal, and oculomotor systems, which allows neuropathological differentiation between these entities. Variability of both clinical and pathological features is mainly related to the patient's age at onset, which is often correlated with the number of CAG repeat size. Several characteristics are suggestive of these SCD: preferential degeneration of specific systems, size reduction at cellular or tissue level not accompanied by glial reaction (simple atrophy or hypoplastic change) and presence of recently identified ubiquitin positive inclusions in neurons are characteristics of these SCDs. These features provide further insight into the phenotypic development of a genetic abnormality.

Based on the hereditary ataxias concepts and a large field survey, the authors analyzed 392 cases of spino-cerebellar degeneration belonging to 188 families. Two main clinical groups were identified: 227 cases of Friedreich ataxia and 74 cases of cerebellar hereditary ataxia of P. Marie type. The association in the same patient of peroneal atrophy of Charcot Marie type with Friedreich ataxia (17 cases) or P. Marie cerebellar hereditary ataxia (13 definite cases and 13 probable) was the most striking finding. "Forme fruste", incomplete form or complex form of Friedreich ataxia were present in some families while in some others there was spastic paraplegia or pure Charcot Marie Tooth disease. This clinical heterogeneity in families of spino-cerebellar degeneration is discussed.

"Energy metabolism" is deranged in a wide variety of disorders of the nervous system. This term refers rather loosely to the pathways responsible for the utilization of the major substrates of brain. Primary disorders of energy metabolism are those in which the primary insult affects the cellular machinery required for energy metabolism. A typical example would be a defect in a gene coding for a mitochondrial protein. Biochemically, defects which appear to be hereditary and which lead to disease of the central nervous system have been described in each of the pathways of energy metabolism: glycogenolysis (the break-down of glycogen to glucose); glycolysis (the break down of glucose to pyruvate and lactate); the pyruvate dehydrogenase complex (which oxidizes pyruvate to enter the Krebs tricarboxylic acid cycle); the tricarboxylic acid cycle itself (which completes the oxidation of carbohydrates and other substrates to carbon dioxide); electron transport (which carries out their oxidation to water); the pentose phosphate pathway (an alternate pathway for glucose oxidation); and several "minor" mitochondrial pathways. Clinically, the spectrum of syndromes associated with primary disorders of energy metabolism is wide. Common manifestations include psychomotor retardation, with associated lactic acidosis and/or hypoglycemia. The laboratory abnormalities may be intermittent. Syndromes which have been culled out include congenital lactic acidosis, Leigh disease, intermittent ataxia, Kearns-Sayre-Shy syndrome (KSS), myoclonus epilepsy with ragged red fibers (MERRF), and mitochondrial myopathy-encephalopathy-lactic acidosis-stroke (MELAS). As with other families of inborn errors, both clinical and biochemical heterogeneity occur. Patients with apparently similar clinical syndromes can turn out to have different inborn errors, and patients with abnormalities of the same gene product can have clinically distinguishable syndromes. Secondary disorders are those in which the derangements of energy metabolism are presumably secondary to some other insult but may still be important for the cellular pathophysiology. These include the metabolic encephalopathies and probably a number of well-known neurodegenerative disorders. In the hereditary ataxias, abnormalities of mitochondrial markers are common but do not correlate consistently with the disorders as conventionally classified; a new classification into axonal ataxias, multiple system degenerations, and ataxic encephalopathies may be easier to relate to the pathophysiology.(ABSTRACT TRUNCATED AT 400 WORDS)