Population frequencies of inherited neuromuscular diseases—A world survey

Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

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A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012.

Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4-3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.

Molecular mapping of twenty-four features of Down syndrome on chromosome 21.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder manifest by characteristic brain and eye malformations. We reviewed data on 21 of our patients and an additional 42 patients from the literature. From this review, we expand the phenotype to include congenital muscular dystrophy (CMD) and cleft lip and/or palate (CLP), and revise the diagnostic criteria. Four abnormalities were present in all patients checked for these anomalies: type II lissencephaly (21/21), cerebellar malformation (20/20), retinal malformation (18/18), and CMD (14/14). We propose that these comprise necessary and sufficient diagnostic criteria for WWS. Two other frequently observed abnormalities, ventricular dilatation with or without hydrocephalus (20/21) and anterior chamber malformation (16/21), are helpful but not necessary diagnostic criteria because they were not constant. All other abnormalities occurred less frequently. Congenital macrocephaly with hydrocephalus (11/19) was more common than congenital microcephaly (3/19). Dandy-Walker malformation (10/19) was sometimes associated with posterior cephalocele (5/21). Additional abnormalities included slit-like ventricles (1/21), microphthalmia (8/21), ocular colobomas (3/15), congenital cataracts (7/20), genital anomalies in males (5/8), and CLP (4/21). Median survival in our series was 9 months. A related autosomal recessive disorder, Fukuyama congenital muscular dystrophy, consists of similar but less severe brain changes and CMD. It differs from WWS because of consistently less frequent and severe cerebellar and retinal abnormalities. We think that WWS is identical to "cerebro-oculo-muscular syndrome" and "muscle, eye, and brain disease."

Diagnostic criteria for Walker-Warburg syndrome.

Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.

Muscle-eye-brain disease (MEB)

Five patients showing several stigmata of Down's syndrome and a partial trisomy of chromosome 21 are reported Three patients with only a moderate degree of mental retardation had an additional deleted chromosome 21; the characteristic dark G-band region of the long arm of 21 was missing In another patient with a typical Down's syndrome the G-band region and the distal portion of the long arm of 21 were present in excess and were translocated onto the short arm of 15 Clinical features suggestive of Down's syndrome were also seen in a mildly retarded girl with a mosaic chromosome constitution (one cell line had an isochromosome for the long arm of chromosome 21 and the other had a deletion of the short arm of chromosome 21)

By correlating clinical and cytogenetic data on these patients, an attempt was made to analyse the phenotypic effects caused by the presence of excess amounts of different segments of chromosome 21

Partial trisomy 21

Muscular dystrophy, brain changes, severe visual failure, myopia and eye changes consisting of congenital glaucoma, cataract, optic and renal changes, have not previously been grouped together in any known syndrome.



A series of nine children (8 boys and 1 girl) aged 12 months to 10 years, one of whom had died at the age of 6 years, and one adult male patient aged 40 years, are described.



The general signs, laboratory findings and genetic aspects have been presented in detail in a previous paper.



Severe visual handicap, nystagmus and uncontrolled eyemovements were present in 9/10 patients.



Myopia of > 2 D was found in 8/10 and severe myopia (> 10 D) in 6/10 patients. Congenital glaucoma was diagnosed and treated in five children and infantile glaucoma in three children. Glaucoma was caused by defective cleavage of the chamber angle as evidenced by membranes and synechiae of the chamber angle on gonioscopy and by histology. Mature cataract was operated in two patients aged 10 and 23 years, respectively. Microspherophakia was present in two boys.



The ERG and VER showed non-specific changes in the four patients examined. Tapetoretinal dystrophy was not present.



A sequence of muscular dystrophy, brain changes, severe visual failure and eye changes consisting of congenital glaucoma, cataract, optic and retinal changes, has not been found within the range of any hitherto known syndrome.

Ophthalmological findings in a new syndrome with muscle, eye and brain involvement

Muscle-eye-brain disease and Walker-Warburg syndrome.

15 cases of congenital haemolytic anaemia have thus far been attributed to hexokinase (HK) deficiency in erythrocytes. We report some clinical, biochemical and genetic findings from 5 members of a Finnish family with this deficiency. The proband, a 1-year-old girl, was the only patient with anaemia. All subjects had either mild or marked reticulocytosis. Red cell ATP levels were at the lower range of normal in all subjects and 2,3-DPG was abnormally low in one. The activities of red cell enzymes, other than HK, were within or above the normal range, respectively. The Km-values for glucose and fructose were elevated (ATP normal) in the subjects with HK deficiency. We speculate that the family represents heterozygosity of a mutant allele and that there is phenotypic variation associated with the HK mutant. The locus might be subject to mutations which lead to a variety of HK variants and to a spectrum of diseases. This point of view is in accordance with the overwhelming variation of reaction kinetics and metabolic effects of this and other reported cases.

Jaakko Leisti

Papers

Muscle-eye-brain disease (MEB)

Partial trisomy 21

Ophthalmological findings in a new syndrome with muscle, eye and brain involvement

Muscle-eye-brain disease and Walker-Warburg syndrome.

Hexokinase deficiency in erythrocytes: a new variant in 5 members of a Finnish family.