Reijo Norio

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive inherited form of epilepsy, previously linked to human chromosome 21q22.3. The gene encoding cystatin B was shown to be localized to this region, and levels of messenger RNA encoded by this gene were found to be decreased in cells from affected individuals. Two mutations, a 3′ splice site mutation and a stop codon mutation, were identified in the gene encoding cystatin B in EPM1 patients but were not present in unaffected individuals. These results provide evidence that mutations in the gene encoding cystatin B are responsible for the primary defect in patients with EPM1.

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular Protein Transport

Cohen syndrome is an uncommon autosomal recessive disorder whose diagnosis is based on the clinical picture of nonprogressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. We have refined the critical region on chromosome 8q22 by haplotype analysis, and we report the characterization of a novel gene, COH1, that is mutated in patients with Cohen syndrome. The longest transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb. COH1 encodes a putative transmembrane protein of 4,022 amino acids, with a complex domain structure. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell.

PROGRESSIVE MYOCLONUS EPILEPSY

The clinical picture and the progression of the disease in 93 cases of progressive myoclonus epilepsy in Finland were analysed. The disease was familial in 25 out of 67 families. The incidence was calculated to be one in 27000 live‐born children, i.e. three new cases each year. The early development and health of the patients was normaI. The first obvious symptom of the disease occurring at the age of 6 to 15 years was either myoclonus or grand mal seizures, the other following later. The characteristic clinical picture also included ataxia, intention tremor, dysarthria as well as emotional lability, but only a slight decrease in the intelligence level. Raised arterial pressure was seen in 14 per cent of cases. Symptoms from other organs were generally lacking. Resistance to infectious diseases seemed to be lower than normally. The thickness of the skull was increased but other disturbances of hone were not found. The pneumoencephalograms did not show any clear atrophy of the brain. The most essential feature of the disease was myoclonus which was provoked by light, touch and other stimuli and it was an important sign for the diagnosis. The increase of myoclonus finally made the patient unable to move unaided and to take care of himself and rendered him bedridden and helpless, most frequently at the age of 17 to 18 years. The average age at death was 24 years, about 14 years after the appearance of the first symptoms. In some patients the progress of the disease came to a halt after many years and these patients sometimes lived for up to 20–30 years after the beginning of the disease. A thorough neuropathological examination was made in one case and in five other cases some autopsy specimens from the brain were examined. Biopsy specimens from other tissues such as peripheral nerves, liver and muscle were examined in 26 cases. The most outstanding feature of the brain was loss of Purkinje cells. No Lafora bodies were found and no other signs of pathological accumulating material. Thus the Finnish cases of progressive myoclonus epilepsy do not belong to the Lafora body type of the disease. Clinically they differ from this type mainly on the basis of the fairly high intelligence level.

Finnish Disease Heritage I: characteristics, causes, background.

This review of the Finnish Disease Heritage (FDH), a group of rare hereditary diseases that are overrepresented in Finland, includes the following topics: FDH characteristics, causes and background, primary theory, revis(it)ed theory, consanguineous marriages in Finland, internal migration of the 1500s, family series for further FDH studies, geography and population structure as a basis for FDH, geography of individual diseases, the structure of FDH families, family structure in individual diseases, Finnish gene mutations, linkage disequilibrium and haplotypes, age of gene mutations, frequencies of disease genes and carriers, and a short description of the possible future of FDH.

Progressive myoclonus epilepsy: genetic and nosological aspects with special reference to 107 Finnish patients

In 107 Finnish patients with progressive myoclonus epilepsy (PME), belonging to 74 families, autosomal recessive inheritance was evident. The sex ratio was 48:51, the corrected proportion of affected sibs being 0.260. Of 68 marriages 15, or 22 %, were consanguineous; several of the parents were related and the geographical distribution was of the uneven type typical of young, isolated populations in Finland. The incidence in Finland was estimated to exceed 1:20,000.

Finnish Disease Heritage II: population prehistory and genetic roots of Finns

In the second part of my review of the Finnish Disease Heritage (FDH), I discuss the settling of Finland; factors influencing the genes of a population, such as agriculture versus hunting/fishing/gathering, trading and cultural relations, wars and other kinds of violence, and bottlenecks; relatives of the Finns in the light of classical European studies, classical Finnish studies, mtDNA and Y-chromosomal studies; the genes of the Finns today, characterizing FDH, the east-west difference among Finns, and minorities in Finland, viz. the Lapps or Saami and Swedish-speaking Finns.

Congenital Nephrotic Syndrome

Congentital nephrotic syndrome (CNS) is an uncommon disorder. Several different diseases may cause the syndrome. These may be inherited, sporadic, acquired or part of a general malformation syndrome. The problems associated with nephrotic syndrome in early infancy are divided into three parts: diagnosis, treatment and prenatal diagnosis. Accurate diagnosis is essential for the treatment, genetic counselling and prenatal diagnosis. The ultimate curative treatment of CNS is renal transplantation. The supportive treatment before the transplantation is of utmost importance in order to maintain a reasonable clinical condition and prepare the child for the dialysis and renal transplantation. Prenatal diagnosis is possible in some types of CNS by determination of the maternal serum and amniotic fluid alpha-fetoprotein (AFP). Increased AFP indicates fetal proteinuria, and thereby nephrotic syndrome before birth. In some cases with the onset of proteinuria after birth prenatal AFP measurement does not detect the disease.

The hydrolethalus syndrome: delineation of a “new”, lethal malformation syndrome based on 28 patients

We describe a lethal malformation syndrome in 28 newborn infants from 18 families. The main manifestations were hydrocephalus (often with an unusual structure of the brain and the occipital bone), very small mandible, Polydactyly, congenital heart defect, abnormalities of the respiratory organs, and (different from the Meckel syndrome) normal kidneys. Polyhydramnios and stillbirth or neonatal death were the rule. Autosomal recessive inheritance is evident. This syndrome is another in the group of rare recessive disorders which are found in Finland. Because of the 25 % recurrence risk and possibilities for prenatal diagnosis, this syndrome should be recognized by paediatricians and, because of the frequent stillbirths, also by obstetricians and pathologists. The name hydrolethalus syndrome (hydramnios, hydrocephalus, lethality) may be of help in this.

Cohen syndrome: Essential features, natural history, and heterogeneity

This article elucidates the clinical picture in Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on the typical clinical picture: nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish patients were investigated. Magnetic resonance images of the brain with quantitative structure analyses revealed a relatively enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all others had low-voltage EEGs. Of the patients, 22% had profound, 61% severe, 6% moderate, and 11% mild retardation. In an adaptive behavior scale (AAMD), patients had high scores in the positive domains (self-direction, responsibility, and socialization), whereas maladaptive behavior was almost lacking. Only the youngest patients had unimpaired visual function. Vision started to deteriorate early but slowly. Progressive myopia and retinochoroidal dystrophy were found in all of the patients over 5 years of age. All of the patients had isolated granulocytopenia. The heart anatomy was normal. However, decreased left ventricular function with advancing age was found. No significant endocrine abnormalities were discovered. Fingers were slender but short, with a typical metacarpophalangeal pattern profile. The manifestations vary at different ages. The Finnish Cohen patients are clinically highly homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed to have Cohen syndrome.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome

We describe 14 patients, from 11 families, who have a progressive encephalopathy with early onset. The clinical signs of the disease are severe hypotonia, convulsions with hypsarrhythmia, profound mental retardation, hyperrcflexia, transient or persistent edema, and optic atrophy. These findings and the characteristic dysmorphic features allow recognition of these patients, although no basic metabolic defect has been found. Microcephaly and atrophy of the brain develop, especially in the cerebellar and brain stem areas. An autosomal recessive mode of inheritance is likely.