Propionic acidaemia: a neuropathological study of two patients presenting in infancy.

The clinical and neuropathological findings are described in two children with propionic acidaemia presenting in infancy; they survived for 4 and 16 years respectively. Abnormalities were noted in the basal ganglia of both patients. In one child who clinically had severe athetosis, there was marbling of the corpus striatum. Clinical and morphological evidence suggests that the basal ganglia are especially vulnerable in propionic acidaemia.

Familial olivopontocerebellar atrophy with neonatal onset: a recessively inherited syndrome with systemic and biochemical abnormalities.

Clinical and pathological findings are reported in two siblings who presented in the neonatal period with failure to thrive, hypotonia, pericardial effusions, limitation of joint movement, retinal dystrophy and loss of visual function. Additional features were biochemical evidence of purine overproduction and liver dysfunction. Post mortem, the neuropathological findings in both children were typical of olivopontocerebellar atrophy. It is suggested that the cases represent a recessively inherited inborn error of metabolism.

Progressive neuronal degeneration of childhood (PNDC) with liver disease.

Thirteen children with progressive neuronal degeneration and liver disease are reported. Clinical features included developmental delay after a normal initial period with later onset of intractable epilepsy. The EEG showed an unusual but characteristic pattern, and visual evoked responses (VER) were abnormal. Rapidly progressive cerebral atrophy was seen on computerized axial tomography (CAT). Inheritance was consistent with an autosomal recessive trait. Pathological findings were neuronal degeneration and spongy change of the cerebral cortex. The calcarine cortex was more severely affected than other areas. Hepatic lesions included severe fatty change and cirrhosis. In six patients liver disease was detected before the onset of epilepsy and exposure to anticonvulsants. Two others were reported to have died from sodium valproate (SV) toxicity, but both had abnormal liver enzymes before treatment with SV, and in both the neuropathological findings were indicative of PNDC. During life, PNDC may be indicated by the characteristic clinical course, abnormal liver function tests, and abnormalities of EEG, VER, and CAT.

Astrocytoma as a second malignancy in patients with acute lymphoblastic leukemia.

Three cases of astrocytoma, two cerebral (grades II and III) and one spinal (grade II) occurring as second malignancies in patients with previously diagnosed acute lymphoblastic leukemia are described. All had received prophylactic cranial irradiation and intrathecal methotrexate. All were in remission at the time of development of the second malignancy. The time interval between central nervous system (CNS) prophylaxis and symptoms of CNS tumor was between 3 and 5 years. The possible causes of the combination of astrocytoma with acute lymphoblastic leukemia are discussed.

Progressive neuronal degeneration of childhood with liver disease. A pathological study.

A clinicopathological study of 10 cases of progressive neuronal degeneration of childhood is reported. In the typical clinical course early developmental delay is followed by intractable epilepsy leading rapidly to death, in some cases in liver failure. Diagnostically useful investigations include characteristic EEG changes, evidence of progressive atrophy (particularly occipital) on CT scan, absent or reduced visual evoked responses, and biochemical evidence of abnormal liver function in many cases before commencement of anticonvulsant therapy. Siblings of 4 of the reported cases suffered a similar clinical disorder. Macroscopic appearances of the brain varied from virtual normality to severe atrophy. The cortical ribbon showed patchy lesions, but the calcarine cortex was characteristically involved, narrowed, granular and discoloured. Histological damage to the cerebral cortex was widespread but patchily accentuated. In milder lesions status spongiosus, astrocytosis and neuronal loss occurred only in the superficial cortex, in moderately affected areas deeper laminae were involved, and in the most severe lesions the entire cortex was reduced to a thin densely gliotic remnant. There was a pronounced tendency for the striate cortex to be the worst affected area. Of subcortical structures the thalamus, hippocampus and cerebellum were particularly severely involved. There was usually accompanying liver disease, particularly a subacute hepatitis comprising massive fatty degeneration, hepatocyte loss, bile duct proliferation and fibrous scarring, with or without cirrhosis. These pathological features are distinct from other combined degenerations of liver and brain and the cortical lesions differ significantly from the neuropathological sequelae of birth injury or severe epilepsy. Hepatic pathology is distinctive and does not appear to be related to drug therapy. It is concluded that these 10 cases of progressive neuronal degeneration of childhood with concomitant liver disease, together with a small number of previously reported cases, are a nosological entity which may result from an autosomal recessive inherited metabolic defect, the nature of which is at present obscure.

Cortical subacute necrotizing encephalomyelopathy. A study of two patients with mitochondrial dysfunction.

Two patients are reported who presented with progressive impairment of neurological and intellectual function, and intractable fits. In both the disease ran a fluctuating course. There was evidence of mitochondrial dysfunction, serum levels of pyruvate and lactate being four to six times normal. Involvement of mitochondria in different organs was suggested by histochemical and ultrastructural investigations of muscle and heart tissue. The children died at nine years and twelve months, respectively. In both autopsy revealed cardiomyopathy and renal abnormalities. The brain showed severe lesions indistinguishable from subacute necrotizing encephalomyelopathy (SNE), the brunt of which was borne by the cortex.

Ornithine carbamoyl transferase deficiency: a neuropathological study.

A detailed autopsy study of three children with ornithine carbamoyl transferase (OCT) deficiency is presented. Although variable in extent, a basic pattern of neuropathological lesions is discernible. Case 1 shows gross cerebral atrophy, cases 2 and 3 milder lesions in the basal nuclei but also multiple cerebellar heterotopias and delayed myelination. We suggest that the findings may provide evidence that OCT deficiency can have a teratogenic effect in utero and suggest that there is a need to monitor the pregnancies of carriers of this disorder.

Involvement of the central nervous system in congenital muscular dystrophies.

Three children, two siblings and one unrelated child, with congenital muscular dystrophy with central nervous system (CNS) involvement are discussed. The siblings appeared to suffer from a relatively mild myopathy with progressive brain disease, of which brain biopsy in one showed astrocytic proliferation in the white matter. In the patient with severe muscle disease, autopsy showed widespread patchy demyelination in the white matter and developmental abnormalities in the cerebral and cerebellar cortex. These patients differ from the Japanese (Fukuyama) cases of CMD in the severity of the changes in the cerebral white matter, and from Santavuori's cases in the absence of ocular abnormalities and hydrocephalus. Their unique nosology is discussed.

Mitochondrial cytopathy or Leigh's syndrome? Mitochondrial abnormalities in Spongiform encephalopathies.

A boy with mitochondrial cytopathy and neuropathological changes of subacute necrotizing encephalopathy is reported. Conditions with abnormal mitochondria in muscle and/or brain are reviewed and the role of mitochondrial abnormalities in spongiform encephalopathies is discussed. It is suggested that electronmicroscopical and histochemical investigations of muscle tissue would be of value in patients with Leigh's syndrome or other forms of spongiform encephalopathies.

Traumatic transection of the brainstem.

A case of nearly complete transection of the lower brainstem following skull fracture with detailed histological study is presented.

Striatal degeneration in childhood.

The clinical features, and the radiological and neuropathological findings of 3 unrelated children with striatal degeneration are presented. In one case the father had recently developed choreiform movements while in the other two the family history was negative for neurological disorders. Two patients had juvenile onset of psychiatric symptoms, seizures, and rigidity. The 3rd child presented with focal seizures at 9 weeks of age. The neuropathological findings are virtually identical in all 3 cases. The classification of striatal degeneration in childhood is discussed.

Fetal damage despite low-phenylalanine diet after conception in a phenylketonuric woman.

A woman with phenylketonuria gave birth to an infant with a cardiac defect and microcephaly despite introduction of a low-phenylalanine diet 5 weeks after conception (3 weeks after the first missed period). In maternal phenylketonuria fetal damage leading to reduced brain growth and cardiac malformations probably occurs within a few weeks of conception.

Extradural haemangiolipoma in the spinal canal. Two cases presenting during pregnancy.

Extradural spinal haemangiolipomas are very rare but they account for forty per cent of all lipomas in this position. The two cases described here were middleaged women who both had a paraparesis during their pregnancy which remitted after parturition. Both tumours were in the thoracic region on the posterior surface of the dura. The histological appearances were those of a lipoma with a definite capillary component. The pathogenesis of the relapsing and remitting paraplegia and its relationship with pregnancy is probably multi-factorial. It is proposed that both blood volume and extra-cellular fluid volume changes occurring during pregnancy may be responsible for the fluctuating cord compression. Similarly the hypothesis is put forward that due to the vascularity of the tumour it exerts a "steal" phenomenon over the blood supply to the adjacent cord. Also, because of its vascularity, the tumour could have a pulsatile compressive effect on the cord.

Cerebral malformation associated with metabolic disorder. A report of 2 cases.

A clinical and neuropathological study is presented of two cases each of which showed neuronal heterotopia. Microgyria was also present in one case. One patient was suffering from a degenerative disorder affecting the white matter. The other was a case of Menkes' disease. It is suggested that the antenatal damage may have been caused by an imbalance of the maternal metabolism, the predisposing factor being the mother's carrier state for a metabolic defect. This is the first report of teratogenesis in a case of Menkes' disease. It is also noted that in this case there is interference with the postnatal as well as the antenatal development of the brain.