Adam N. Bender

Mitochondrial Neurogastrointestinal Encephalomyopathy Syndrome Maps to Chromosome 22q13.32-qter

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphorylation and multiple mtDNA deletions frequently in skeletal muscle. We studied four ethnically distinct families affected with this apparently autosomal recessive disorder. Probands from each family were shown, by Southern blot, to have multiple mtDNA deletions in skeletal muscle. We mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum two-point LOD score of 6.80 at locus D22S526. Cosegregation of MNGIE with a single chromosomal region in families with diverse ethnic backgrounds suggests that we have mapped an important locus for this disorder. We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase.

Chronic GM2 gangliosidosis masquerading as atypical Friedreich ataxia Clinical, morphologic, and biochemical studies of nine cases

A progressive spinocerebellar degenerative disorder was characterized in nine patients, aged 11 to 37 years, from four unrelated Ashkenazi Jewish families; affected individuals had markedly deficient β-hexosaminidase A activity. Symptoms included early onset of cerebellar signs (tremor, incoordination, and dysarthia) and, with maturity, the development of upper and lower motor neuron disorders, marked dysarthria, and ataxia. Three older patients, aged 26, 32, and 37 years, had dementia or recurrent psychotic episodes. Membrane-bound lamellar cytoplasmic inclusions, consistent with lysosomal ganglioside accumulation, were observed in rectal ganglia. The activity of β-hexosaminidase A was markedly deficient in all sources analyzed. Parents had activities consistent with heterozygosity, confirming autosomal-recessive transmission of the β-hexosaminidase A-deficient gene and the adult variant disorder. Residual β-hexosaminidase A activity, partially purified by anion-exchange chromatography from cultured skin fibroblasts of the affected individuals, was heat-labile and co-electrophoresed with normal β-hexosaminidase A. These findings suggest that these patients were allelic for a new β-hexosaminidase A mutation and may represent a genetic compound of this allele and the allele causing Tay-Sachs disease.

Thymomas in patients with myasthenia gravis.

The records of 141 patients with myasthenia gravis who had thymomas were reviewed. In this series there were 69 noninvasive tumors and 52 invasive tumors. The five year survival for all patients was 60%, with the invasive group demonstrating a poorer prognosis than the noninvasive. The remission rates for the whole group (both invasive and noninvasive) of myasthenics was quite low (7%). Although the overall survival of this series of patients was relatively high, it is felt that by earlier diagnosis and a more aggressive surgical approach their prognosis will be even better.

Cholinergic dysautonomia and Eaton-Lambert syndrome.

Cholinergic autonomic function was abnormal in a 47-year-old woman with Eaton-Lambert syndrome (ELS), not associated with carcinoma. Pupillary constriction to light and accommodation, sweating, lacrimation, and salivation were all affected. There was no evidence of Sjogren syndrome or botulinum intoxication. The defect of acetylcholine release from presynaptic terminals in the Eaton-Lambert syndrome may not be restricted to the neuromuscular junction of skeletal muscle.

Hypokalemic periodic paralysis exacerbated by acetazolamide

Although acetazolamide usually prevents paralytic attacks in hypokalemic periodic paralysis, not all patients benefit from this treatment. We studied a father and two sons in whom attack frequency and severity increased on acetazolamide. Administration of triamterene virtually abolished attacks in three separate single-blind trials totaling more than 12 months. Spontaneous and glucose-insulin provoked attacks occurred with only slight hypokalemia. Acetazolamide produced slight hypokalemia and provoked attacks of weakness whereas triamterene increased potassium levels significantly. Certain patients with hypokalemic periodic paralysis are worsened by acetazolamide, perhaps because of its kaliopenic effect. Triamterene may be effective in some of these patients.

Muscle fiber hypotrophy with intact neuromuscular junctions A study of a patient with congenital neuromuscular disease and ophthalmoplegia

An infant born with severe but nonprogressive somatic and cranial muscle weakness including bilateral external ophthalmoplegia was studied with a motor-point muscle biopsy. There was a striking generalized decrease in the size of muscle fibers (hypotrophy), most marked in the type I fibers. Many of the small fibers were immature, resembling myotubes. Neuromuscular junctions on severely hypotrophic fibers were normal with esterase staining and by ultrastructural criteria. Although these are unusual clinical and biopsy characteristics, this infants condition bears a resemblance to two other congenital nonprogressive neuromuscular diseases: myotubular myopathy and congenital fiber type disproportion. In these conditions and in our patient, there is no primary degenerative process affecting nerve or muscle but, rather, an apparent lack of maturation of fetal muscle fibers, indicating a defective normal trophic interaction between nerve and muscle.

Muscle phosphofructokinase deficiency: biochemical and immunological studies of phosphofructokinase isozymes in muscle culture

Muscle cultures from three unrelated patients with muscle phosphofructokinase (PFK; EC 2.7.1.11) deficiency (Glycogenosis type VII; Tarui disease) had normal PFK activity and normal morphology. Chromatographic and immunological studies showed that normal muscle cultures express all three PFK subunits, M (muscle-type), L (liver-type), and P (platelet-type) and contain multiple homotetrameric and heterotetrameric isozymes. Muscle cultures from patients lack catalytically active M subunit-containing isozymes, but this is compensated for by the presence of P- and L-containing isozymes. Despite the lack of muscle-type PFK activity, presence of immunoreactive M subunit was demonstrable by indirect immunofluorescence, suggesting a mutation of the structural gene coding for the M-subunit of PFK.

Autonomic neuropathy associated with autoimmune disease

Mononeuropathy multiplex and mixed sensorimotor neuropathy are known complications of systemic vasculitis and related autoimmune disorders. Autonomic dysfunction is not generally considered a neurologic complication of these diseases. We report two patients who came to neurologic attention because of autonomic dysfunction and were then discovered to have autoimmune disease. Autonomic dysfunction may be the presenting sign of autoimmune disorders, which should be considered in the differential diagnosis of acquired autonomic disturbances.

Acetylcholine receptors of aneurally cultured human and animal muscle

We describe the diffuse nonjunctional distribution of AChR molecules of aneurally cultured human and animal muscle and the influence of sera from myasthenia gravis patients and rabbits with experimental autoimmune myasthenia gravis on binding of αBT to diffuse nonjunctional AChR. One-hour incubation of myasthenia gravis sera resulted in blocking of the α-BT-immunoperoxidase staining of their AChRs, while incubation in normal sera did not. Aneurally cultured muscle can aid studies of regenerating fibers in normal muscle compared with those of muscles in neuromuscular diseases, and also act as an environmentally controlled test object for demonstrating the effect of circulating pathogenic factors.