Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

https://science.sciencemag.org/content/sci/271/5254/1423.full.pdf

Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion

Population frequencies of inherited neuromuscular diseases—A world survey

DNA duplication associated with Charcot-Marie-Tooth disease type 1A

Classification of the hereditary ataxias and paraplegias

The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

https://www.physiology.org/doi/pdf/10.1152/physrev.00030.2008

Mitochondrial Dynamics in Mammalian Health and Disease

The prevalence of Charcot-Marie-Tooth's disease (CMT) was studied in Western Norway, an area with several isolated districts with a population of 725,000 (1968). Three hereditary types were distinguished in the area: autosomal dominant CMT with an estimated prevalence of 36/100,000; X-linked recessive CMT with a prevalence of 3.6/100,000; and autosomal recessive CMT with a prevalence of 1.4/100,00. Gene frequencies were 3 · 7. 10-4, 1 · 9. 10-4, and 4 · 8. 10-4 in autosomal dominant, X-linked, and autosomal recessive CMT, respectively, while the corresponding mutation rates were 13 · 0, 5 · 5, and 3 · 5 per million gametes per generation. The penetrance was almost complete for all three variants of CMT.



Strict diagnostic criteria were followed in the selection of the 37 index cases. A family investigation was carried out with 238 subjects, during which 69 secondary cases were detected. Another 57 subjects had unspecific neuropathy (Un), which did not fit a diagnosis of CMT or other neurological disease. In the diagnosis of Un, a score system was used, with age and sex corrections based on findings in a normal population.



Generally, the most severe disease course was found in the recessive CMT types, but there was also more clinical variation, suggesting CNS involvement in some cases (upper motor neuron affection, cerebellar signs). Scoliosis and spinal ataxia were not infrequent, even in cases with autosomal dominant CMT.



The prevalence cf Un was highest in the relatives of recessive CMT cases, with a ratio of affected to normal in sibs compatible with a hypothesis of several cases of heterozygous manifestation. In the relatives of autosomal dominant CMT cases, Un prevalence was also higher than in the population, but lower in 2nd degree relatives than in 1st degree; the ratios fitted a hypothesis of polygenic Un inheritance. Significant differences were found in the score patterns of Un in the recessive CMT families and in the autosomal dominant families, suggesting their difference of origin. The reason for clustering of Un cases in autosomal dominant CMT families is obscure, since it can be only partly attributed to early manifestation of CMT. It is suggested that Un and CMT, mainly in autosomal dominant CMT, interact to form a spectrum of differing phenotypes, so explaining the problem of “transitional forms” between CMT and other hereditary nervous disorders. Recessive CMT, being a more generalized nervous disease, attains, through differing expressivity, phenotypes which vary between individual cases.

Genetic and clinical aspects of Charcot‐Marie‐Tooth's disease

The prevalence of neurological signs in the normal population was investigated in order to establish their significance when found in patients. The traditional neurological examination is characterized by the registration of various reflexes, motor and sensory performances, and perceptual functions. An attempt was made to transform neurological information into quantitative units, making it possible to employ statistical methods. This system was applied to a randomized population sample drawn from 5 equally sized 10-year groups of adults, totalling 373 subjects. A characteristic age- and sex-dependent sum score pattern emerged, showing similarities with other investigations using different parameters for the registration of physiological age. The changes increased more evenly by age in men than in women, and started at an earlier age. The symptoms of ageing were rather stereotyped, consisting of minor pareses, deformities, and proprioceptive disturbances in feet and hands, and slight ataxic signs. However, the extent of individual involvement varied within wide limits. Very few were unaffected past 65. Men displayed more extensive changes in high age than women, who on the other hand were more affected in middle age. Further, the menopausal period seemed to coincide with changes largely reversible, including CNS symptoms. Social differences were also reflected through the sum scores, poor socio-vocational status being associated with higher sum scores in males past 40. The sum score differences between socio-vocational levels were apparently not due to working conditions. It has been speculated that innate biological or perinatal factors may be important determinants of the subsequent integrity of the CNS.

Neurological signs in a normal population.

In Western Norway, two types of hereditary spastic paraplegia (HSP) were found: one type segregating as an autosomal dominant, and the other type behaving as an autosomal recessive trait. Within the last category, an infantile type might be defined, with more marked CNS affection than usual (dementia, epilepsy, cerebellar signs). In two of five families with autosomal recessive HSP, retinitis pigmentosa was found in the affected persons. Muscular atrophy was frequently found in both types of HSP, but was more pronounced in the recessive form. Cerebellar signs and cerebral/mental dysfunction also occurred relatively frequently in recessive cases.



In three kindreds where HSP segregated as a dominant trait, 38 family members were examined. Of these, 23 were affected, four had unspecific neuropathy (Un), and 11 were unaffected. In five families where HSP behaved as a recessive trait, 61 family members were examined. Eleven were affected, 19 had Un, and 31 were unaffected. In the diagnosis of Un, a score system was used recording all types of neurological sign. The scores were corrected for age and sex differences based on findings in a normal population.



Estimated prevalence in the area studied was 12/100,000 for autosomal dominant HSP and 2/100,000 for autosomal recessive HSP. There was a high consanguinity rate in the recessive families, so the prevalence here does not reflect the general gene frequency, which was estimated to be 1 · 2.10-4 (9.7.10-5 in dominant HSP). The distribution of Un in HSP families suggested different etiologies. Ratios in the recessive HSP families indicated Un to be a heterozygous manifestation. The prevalence in dominant families fitted the hypothesis that Un occurs here as a polygenic trait. Clinical differences in Un also supported these conclusions.

Hereditary spastic paraplegia in Western Norway

Friedreich's ataxia (FA) was investigated in Western Norway, an area comprising several isolated communities and with a population of 725,000 as at 1 January 1968. The prevalence of FA was estimated to be 1/100,000 in this population. An autosomal recessive mode of transmission appeared likely in all instances.



The gene frequency was only 7.9.10--5, but the consanguinity rate was high in the families observed. The mutation rate was relatively high at 1.6.10--5.



The clinical features displayed by the 10 examined patients agreed well with those observed by other investigators. Spinal and cerebellar ataxia dominated the clinical picture. In most cases signs of peripheral neuropathy were also observed. Epilepsy was seen in some cases, and also dementia.



Unspecific neuropathy, defined according to a scoring system may represent disease manifestation in FA heterozygotes.

Friedreich's ataxia in Western Norway

Marinesco-Sjogren syndrome and hypergonadotropic hypogonadism were observed in two kindreds, and they were found to occur togetherin 9 out of 10 affected individuals. The last patient had Marinesco-Sjogren syndrome without manifestations of hypogonadism, and similar findings were observed in two affected sisters from a third kindred. On the hypothesis that the concurrence of Marinesco-Sjogren syndrome and hypergonadotropic hypogonadism was caused by linkage, a lod score analysis was conducted. Four sibships in the two kindreds were informative with respect to linkage. At the recombination fraction 0.05, the lod score exceeded 3. If linkage causes the concurrence of Marinesco-Sjogren syndrome and hypergonadotropic hypongonadism in these kindreds, the linkage is close. No linkage was observed between the clinical syndromes and 17 marker systems.

H. Skre

Papers

Genetic and clinical aspects of Charcot‐Marie‐Tooth's disease

Neurological signs in a normal population.

Hereditary spastic paraplegia in Western Norway

Friedreich's ataxia in Western Norway

Linkage studies on the Marinesco-Sjøgren syndrome and hypergonadotropic hypogonadism