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352
Abstracts
SY-02-2
Recent advances in congenital muscular dystrophies
I. Nonaka, Y.K. Hayashi, H. Ishikawa, K. Sugie, F.
Uematsu, I. Nishino
National Center of Neurology and Psychiatry, Tokyo, Japan
Congenital muscular dystrophy (CMD) has been classified
into two major groups: Fukuyama type CMD (FCMD)
and classical CMD (non-FCMD). FCMD is prevalent in the
Japanese, comprising 1–2/100 000 population and characterized
clinically by muscle hypotonia and weakness from
early infancy and central nervous system abnormalities. The
gene for FCMD has been mapped to 9q31 and the gene
product, fukutin, consists of 461 amino acids, but its function
is unknown. Since immunoreactivity to alpha-dystroglycan
was deficient, the fukutin gene mutation is probably
related to altered glycosylation, which may lead to disruption
of the transmembranous molecular linkage. The classical
form of non-FCMD has been further subdivided into
several distinct forms, including merosin deficiency,
muscle-eye-brain (MEB) disease and congenital atonicsclerotic
muscular dystrophy (Ullrich’s disease). We have
studied nine patients with Ullrich’s disease clinically and
pathologically. From early infancy, all patients had proximal
joint contractures, including limited neck flexion and
kyphoscoliosis, and distal joint hyperlaxity. Although four
patients learned to walk, the disease is slowly progressive.
One patient had a complete collagen VI deficiency immunohistochemically
and compound heterozygous mutation in
the COL6 gene. The other eight had partial collagen VI
deficiency immunohistochemically.
SY-02-3
Mitochondrial myopathies
S. DiMauro
Columbia University College of Physicians and Surgeons,
New York, NY, USA
The ‘molecular era’ of mitochondrial myopathies started
in 1988 with the discovery of the first mutations in mitochondrial
DNA (mtDNA). The small circular molecule of
mtDNA turned out to be a Pandora’s box of pathogenic
mutations, which have been associated with a bewildering
variety of clinical syndromes. From a genetic point of
view, mtDNA mutations can be divided into two groups:
those affecting mitochondrial protein synthesis in toto; and
those affecting specific proteins of the respiratory chain. In
recent years, interest has shifted towards Mendelian genetics,
a shift justified by the fact that most proteins of the
respiratory chain are encoded by nuclear DNA (nDNA). In
addition, proper assembly and function of respiratory chain
complexes requires numerous nDNA-encoded ancillary
proteins, whose mutations cause mitochondrial encephalomyopathies
(‘murder by proxy’). Because mtDNA is the
slave of nDNA, numerous nuclear factors are needed to
insure mtDNA replication and to preserve mtDNA integrity.
Mutations in these factors impair intergenomic
communication and result in syndromes characterized by
mtDNA multiple deletions, mtDNA depletion, or both
together. Within the past year, mutations in four genes
have been associated with autosomal dominant or recessive
forms of progressive external ophthalmoplegia and multiple
mtDNA deletions, and mutations in two genes have
been associated with mtDNA depletion syndromes. Finally,
new pathogenetic concepts are being introduced. For
example, alterations of the respiratory chain may be due
to altered composition of the inner mitochondrial
membrane (IMM) lipid milieu. This is the case of Barth
syndrome, an X-linked recessive mitochondrial myopathy/
cardiopathy characterized by severe deficiency of cardiolipin,
the major phospholipid of the IMM.
SY-02-4
Lipid storage myopathies
I. Tein
Division of Pediatric Neurology, Hospital for Sick Children,
Canada
Genetic defects in fatty acid oxidation (FAO) are an
important group of infancy- or childhood-onset disorders
because they are potentially rapidly fatal and a source of
major morbidity. FAO defects encompass a spectrum of clinical
disorders including progressive lipid storage myopathy,
episodic myoglobinuria, neuropathy, pigmentary retinopathy,
progressive cardiomyopathy and recurrent hypoglycemic,
hypoketotic encephalopathy or Reye-like syndrome
with secondary seizures and potential developmental delay.
Recurrent myoglobinuria may be seen in carnitine palmitoyltransferase
II, carnitine acylcarnitine translocase, long- and
very long-chain acyl-CoA dehydrogenase, short-chain l-3-
hydroxyacyl-CoA dehydrogenase and long-chain l-3-hydroxyacyl-CoA
dehydrogenase or trifunctional protein deficiencies.
As all of the known FAO defects are inherited as
autosomal recessive diseases, there is oftentimes a family
history of sudden unexpected death or sudden infant death
syndrome (SIDS) in siblings. Early recognition and prompt
initiation of therapy, as well as institution of appropriate
preventive measures, may be lifesaving and significantly
decrease long-term morbidity, particularly with respect to
neurological sequelae. There are now at least 17 recognized
defects in FAO, most of which have been diagnosed in the
last 15 years. With significant biomedical advances and
increased index of clinical suspicion, there has been a rapid
increase in the number of diagnosed cases. In a recent survey
from the Pennsylvania newborn screening program, the incidence
of medium-chain acyl-coenzyme A dehydrogenase
deficiency was found to be as high as 1 in 8930 live births.
In order to provide the background for understanding these
disorders, an overview will be given of the pathway of FAO