Gaucher disease‐Norrbottnian type (III)

This investigation was undertaken 1) to study the clinical manifestations, development and course of the Norrbottnian type of Gaucher disease ‐ a type I11 variant ‐ with emphasis on central nervous system symptomatology and function, 2) to correlate clinical signs with laboratory, neuropathological and biochemical findings, 3) to evaluate effects of splenectomy on the course and severity of the disease and 4) to investigate the effect of bone marrow transplantation. Clinical methods applied were neuropaediatric follow‐up examinations, psychometric tests and motor age tests. Conventional neurophysiological, haematological and clinico‐chemical methods were used. The investigation comprised 22 patients, 10 girls and 12 boys, in all of whom the clinical diagnosis was confirmed by enzymatic tests. The median age at diagnosis was 1.9 years. The clinical pattern at diagnosis was usually that of an alert child with normal intelligence, short stature, splenomegaly, a tendency to bleeding and ocular manifestations. The course was slowly progressive but varied considerably between patients. The median age at death in a representative group of patients was 11.8 years. Early motor development was delayed in the lower limbs but normal in the upper. Eight patients later developed ataxia and six patients signs of mild spastic paraparesis which usually appeared many years after splenectomy. IQ tended to decrease with age. Early splenectomy resulted in lower IQ scores than late splenectomy. With progression of the disease, EEG abnormalities became increasingly frequent, more markedly among splenectomized patients. Thirteen patiens had abducens nerve weakness and ten had agedependent abnormalities of horizontal gaze. Retinal infiltrates were characteristic, mainly among splenectomized patients. At, autopsy, Gaucher cell accumulations were found in the adventitia of brain venules, most frequently in cerebral and cerebellar subcortical white matter. Intraneuronal storage of glucosylceramide was observed. The highest concentrations of glucosylceramide were in the cerebellum and cerebral subcortical white matter of splenectomized patients. The fatty acid composition of glucosylceramide from these regions indicated an extracerebral origin in splenectomized patients, but mainly cerebral in nonsplenectomized. Psychosine was found, the highest concentrations in cerebral and cerebellar cortex. Bone marrow transplantation was performed in a nine‐year old girl. A three‐year follow‐up showed very encouraging results both biochemically and clinically. It was concluded that:– The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. – A follow‐up system with subdivision of the natural course into four defined clinical stages was clinically useful. – Early splenectomy resulted in a less favourable clinical course and the spleen should therefore not be removed until the hypersplenic state prompts intervention. – The origin of CNS symptomatology seemed to be related to glucosylceramide produced in other parts of the body and transported to and stored perivascularly in the brain. – Bone marrow transplantation was a satisfactory method for enzyme replacement.