H. H. J. Jaspar

Ophthalmoplegia-plus, a real nosological entity

Four patients with chronic progressive external ophthalmoplegia (c.p.e.o.), retinal, neurological, endocrine and auditory anomalies, three of whom showed signs of cardio‐myopathy, are described. On biochemical examination signs of disturbed pyruvate and lactate metabolism were found and there were indications of loss of respiratory control with loosely coupling of phosphorylation (from oxidation). In the muscle biopsy specimens from all four patients aggregates of abnormal mitochondria were seen, compatible with the diagnosis of a mitochondrial myopathy.

Progressive poliodystrophy (alpers') disease) with a defect in cytochrome in muscle: a report of two unrelated patients

We present two unrelated patients, a boy and a girl, with a progressive neurologic disorder, characterized by psychomotor retardation, seizures and paresis, the illness being exacerbated during stressful periods. Lactate levels in serum and cerebrospinal fluid were elevated in both patients. Histopathologic studies of muscle tissue revealed mitochondrial abnormalities in the boy; in the girl, slight neuronal degeneration was observed. A cerebral biopsy in the girl showed abnormalities compatible with progressive poliodystrophy. Autopsy in the boy demonstrated progressive poliodystrophy. Biochemical studies in muscle tissue showed a defect of cytochrome aa3 in both patients, connected with a defect of cytochrome b in the girl. The association of defective pyruvate metabolism and progressive poliodystrophy is discussed.

A mitochondrial myopathy with a defective respiratory chain and carnitine deficiency

A boy presented suffering from generalised weakness, exercise intolerance and lactic acidosis. The weakness became evident at 2 years. A cerebral CT-scan showed cerebellar atrophy and central and peripheral atrophy of both hemispheres. With trichrome staining about 20% of the muscle fibres showed large areas containing redstaining granular material. Electron microscopic examination showed that this material consisted of areas of mitochondrial proliferation, most of the mitochondria having abnormal ultrastructural characteristics. Pyruvate dehydrogenase complex and citric acid cycle activities were determined by measuring 14CO2 production from various labelled substrates. Diminished oxidation rates were found with the patients muscle homogenate for all substrates tested, indicating a defect in the respiratory chain. The cytochromes were present in normal quantities. Succinate cytochrome c reductase activity was very decreased. Carnitine concentration was decreased in serum and in muscle as well.

Connatal Pelizaeus-Merzbacher Disease with congenital stridor in two maternal cousins

SummaryTwo maternal cousins are described with the connatal form of Pelizaeus-Merzbacher Disease (PMD) and congenital stridor. Study of brain biopsy material confirms the diagnosis of PMD. The neuropathological findings are suggestive for the transitional form of this disease. Quantitative morphology gives support to the hypothesis that PMD is a disturbance in maturation of neurons and in myelin formation rather than an active degenerative process. The hereditary transmission is most consistent with a sex-linked recessive pattern. Different X-linked signs seem combined in the presented cases.

Kearns syndrome: a heterogeneous group of disorders with CPEO, or a nosological entity?

In connection with 4 new cases of Kearns syndrome (multisystem form of mitochondrial CPEO), the condition was found to be present in slight to oligosymptomatic form in all 4 families. The marker symptom in subclinical patients was nearly always ptosis (sometimes very slight) and occasionally diabetes. In the literature other endocrine disorders, retinal anomalies, deafness, growth disturbances, etc., have been noted as subclinical symptoms in former generations. Heredity appears to be autosomal dominant in these 4 families, with very variable expressivity. The possibility that one gene is responsible for the disease seems to be plausible, but the marked variation in expressivity suggests a modifying influence of other alleles; in this sense, therefore, one may speak of multifactor inheritance. Supporting facts could also be found in the literature, where there was autosomal dominant heredity of the disease-carrying gene, but for its complete expression ‘amplifying’ factors (alleles) were needed. The pleiotropia of the disease-carrying gene is explained by a mitochondrial disorder of various organs.On the basis of the heredity, therefore, Kearns syndrome is not a syndrome but a disease. The most serious, most progressive and most extensive (multisystem) variant of Kearns disease is the infantile form, known as the ‘Kearns-Sayre syndrome’. When the expressivity of the disease is less extensive it usually occurs later in life and is less progressive: the adult form of Kearns disease.

Chronic progressive external ophthalmoplegia in a heredo-ataxia: neurogenic or myogenic? A clinical, neuropathological and submicroscopic study.

A patient with Friedreichs disease and chronic progressive external ophthalmoplegia is described. An investigation was performed into the nature of the ocular motor disorders, which appeared clinically to be supranuclear. The EMG of the ocular muscles suggested myopathy. A specimen of ocular muscle was obtained by biopsy and examined with the light microscope and—for the first time—under the electron microscope. Signs of mitochondrial myopathy were found alongside neurogenic features. Postmortem examination of the central nervous system confirmed the diagnosis of Friedreichs disease with lesions of the motor cells in the anterior horn of the spinal cord. No evidence was found for a supranuclear or internuclear origin of the ocular palsies, but 20–30 per cent of the neurons in the nuclei III and IV were atrophic. Lesions of the non‐medullated motor nerve fibres were also visible under the electron microscope. That the origin of the c. p. e. o. in this heredo‐ataxia is neurogenic‐nuclear is postulated on the grounds of the neuropathological and electronmicroscopic findings. Resemblances to the microscopic and submicroscopic appearance of many types of “ocular myopathy” and “ophthalmoplegia‐plus” throw doubt upon the myogenic character of these conditions. Possibly chronic, slowly progressive atrophy in the nuclear areas of the ocular motor nerves must in these cases also be held responsible for the c. p. e. o. Perhaps Moebiuss Kern‐Schwund theory may be revived after 85 years.

Congenital fibre type disproportion

Abstract Four children with congenital fibre type disproportion were described. It was shown that their type I fibres were at least 12% smaller than the type II fibres. There was no increase in the terminal innervation ratio (TIR), but a decreased number of terminal knobs was observed in the biopsy of one child. The distribution of fibre types in the biopsy of another child bears out the notion that the abnormalities as seen in the biopsy can be traced back to the spine.

Mutiple mucosal neuromas, dysautonomia and abnormal intradermal histamine reaction

Abstract With reference to a patient a description is given of the syndrome of multiple mucosal neuromas — a syndrome which seems to be caused by a disturbance in the development of neural crest derivatives. The syndrome was associated with a number of autonomie dysfunctions; this dysautonomia is correlated with the morphological findings in a sural nerve biopsy. The nerve was hypertrophic and showed few changes in the myelinated fibres; the unmyelinated fibres showed a chronic process of degeneration and regeneration, and small unmyelinated axons were found increased in number. It is suggested that the abnormal reaction to an intradermal histamine injection was due to the dysautonomia shown by this patient.