P. G. Barth

AN X-LINKED MITOCHONDRIAL DISEASE AFFECTING CARDIAC MUSCLE, SKELETAL MUSCLE AND NEUTROPHIL LEUCOCYTES

An X-linked recessive disease is reported in a large pedigree. The disease is characterised by a triad of dilated cardiomyopathy, neutropenia and skeletal myopathy. The untreated patients, all boys, died in infancy or early childhood from septicemia or cardiac decompensation. Ultrastructural abnormalities were observed in mitochondria in cardiac muscle cells, neutrophil bone marrow cells and to a lesser extent (0-9%) in skeletal muscle cells. Membrane-bound vacuoles were seen in neutrophil bone marrow cells. Intramuscular fat droplets were increased in type I skeletal muscle fibres. An affected patient had intermittent lactic acidemia, borderline low plasma carnitine, the latter decreasing during periods of illness, and low muscle carnitine (27% pretreatment; 35-40% posttreatment). While on treatment with oral carnitine he had less weakness and no cardiac complaints, but his neutropenia was not affected. Respiratory chain abnormalities were observed in this patients isolated skeletal muscle mitochondria. These were: (1) diminished concentrations of cytochromes c1 + c, b and aa3 to 29, 47 and 64% of the averaged controls, and (2) a lowered P:0 ratio for oxidation of ascorbate + TMPD, with diminished uncoupler stimulated Mg2+-ATPase activity. Muscle AMP deaminase was deficient (5 resp. 17%). Only one previous report (Neustein et al. 1979) on X-linked mitochondrial cardiomyopathy exists, which probably refers to the same entity. Biochemical studies and haematological abnormalities (neutropenia) are reported for the first time.

A new leukoencephalopathy with vanishing white matter

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course

Abstract Recently, we described an as yet unidentified white matter disorder in eight patients which probably has an autosomal recessive mode of inheritance. The disease was characterized by megalencephaly and leukoencephalopathy with onset during the 1st year of life and a delayed onset of slowly progressive neurological dysfunction. No basic biochemical defect could be identified. Brain biopsy was performed in one of the patients and the histopathological findings are described in the present report. A spongiform leukoencephalopathy was revealed, without cortical involvement. Most vacuoles were covered by single five-layered membranes, representing single myelin lamellae. Some vacuoles were partially covered by multilamellar myelin sheaths or oligodendroglial cell extensions. The vacuoles were never found in the middle or inner parts of myelin sheaths, but involved the outermost lamellae of myelin sheaths only, whereas the remainder of the myelin sheats remained undisturbed. The histopathological findings place the disease among the vacuolating myelinopathies, although it is distinct from the well-known forms. Possible pathophysiological mechanisms are splitting of the outermost myelin lamellae at the intraperiod line or a disturbance of compaction of the outermost myelin lamellae at the intraperiod line.

Parabiotic twin syndrome with topical isocortical disruption and gastroschisis

SummaryA case of parabiotic twin pregnancy is described with early fetal co-twin loss and topical isocortical disruption and gastroschisis in the surviving twin. We conclude from this case that early fetal parabiotic twin syndrome (before 16 weeks of gestational age) may cause microgyria and neuronal heterotopia. The cerebral and extracranial findings can be explained as the result of multiple vascular obstructions. Whereas most cases of parabiotic twin syndrome with brain damage involve cystic necrosis, focal hypoplasia with disrupted development in the affected part has been found in the present case. The probable reason in discussed. The roentgenographic analysis of the dead twin fetus is consistent with the period of 13–16 weeks as the likely period in which microgyria and neuronal heterotopia originated in the surviving twin. The present case constitutes one of the rare instances in which neuronal migration disturbance in the human could be dated reliably.

Leukoencephalopathy with swelling in children and adolescents : MRI patterns and differential diagnosis

In children, several neurological disorders are characterised by spongiform leukoencephalopathy. MRI of the brain typically shows white matter swelling, but does not enable differentiation of the various underlying disorders. The aim of this article is optimisation of the diagnostic value of MRI in leukoencephalopathy accompanied by swelling. MRI-based inclusion criteria were met by 20 patients in our database. The images were analysed using a detailed scoring list. In 13 of the 20 patients the clinical diagnosis was known (11 definite and 2 probable diagnoses). Characteristic MRI abnormalities could be defined in these patients. Of the 7 patients without a diagnosis, 5 had identical MRI abnormalities: difuse hemisphere swelling and typical cysts in frontoparietal subcortical white matter and the tips of the temporal lobes. The clinical picture was also similar in these patients, suggesting a similar disease.

Central cortico-subcortical involvement: a distinct pattern of brain damage caused by perinatal and postnatal asphyxia in term infants.

Objective The MR findings in a characteristic pattern of hypoxic-ischemic brain damage in term infants are described. Materials and Methods The MR images of seven patients with cerebral palsy and a specific pattern of central cortico-subcortical cerebral damage were studied retrospectively and correlated with clinical findings. Results All seven patients were born at term. Five of the seven patients had a clear history of severe perinatal asphyxia. All children had severe encephalopathic symptomatology, including spastic tetraplegia, extrapyramidal symptoms, and a mental deficit. The MR showed localized atrophy of the cortex and in addition cystic changes, gliosis, and tissue loss of the adjacent white matter. In all patients, the lesions were band shaped in the left-right direction and characteristically located in areas bordering the central sulcus. The segment of the corpus callosum underlying the affected area was always thin. In some patients, lesions were also found bilaterally in the occipital regions, hippocampus, and basal ganglia. The areas involved match the regions that are known to show active myelination on MR in the term neonate. Conclusion Recognition of this specific pattern on MR in children with cerebral palsy enables the classification of such lesions as resulting from peri- or postnatal asphyxia, even if the perinatal history is unknown or equivocal, and makes other etiologies less likely. Index Terms Infants—Central nervous system—Brain—Asphyxia—Brain, ischemia—Magnetic resonance imaging.

Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival

Objective: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS). Methods: The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations. Results: Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation. Conclusions: MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.

Subependymal nodular heterotopia in patients with encephalocele

Only incidental mention has been made to date of the combined occurrence of subependymal heterotopia and posterior encephalocele. We evaluated the presence of disseminated nodular subependymal heterotopia in two series of patients with posterior encephalocele. The first series consisted of all six patients who were treated in our hospital for encephalocele during the last 11 years and who underwent magnetic resonance imaging (MRI). In three, subependymal nodular heterotopia was found by MRI. The second series consisted of eight autopsy cases with encephalocele, representing all cases of encephalocele that came to autopsy during a 10-year period on whom full microscopic examination could be performed. Nodular heterotopia was found in four. The combined occurrence of these two rare conditions may not be accidental.