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Gaucher's disease1 is caused by a deficiency in glucocerebrosidase which gives rise to the accumulation of glucosylceramide (glucocerebroside) in the lysosomes of cells mainly found in the reticuloendothelial system. Type 1, the chronic adult form, is the most frequent, and characterised by splenomegaly, hepatomegaly, pancytopenia, and skeletal degeneration, but does not involve neurological manifestations. Type 2, also called acute neuronopathic, is an early infantile form, usually terminating life in 1 or 2 years. Type 3 is a chronic form which affects the nervous system, usually in late childhood or adolescence. We report here the case of a patient with Gaucher's disease who was diagnosed in early infancy (6 months) in a paediatric institution. He was followed up again between the ages of 26 and 34, a period during which he benefited from enzyme substitutive therapy.
This male patient had no familial history of Gaucher's disease. Pregnancy and birth were normal. At 6 months, he presented with dysfunction of ocular motility in the vertical gaze, oculocephalic asynergy, hepatosplenomegaly, and was found to carry Gaucher's cells in his bone marrow. Abnormal gait and pyramidal signs followed around 4 years of age. There was a macular cherry red spot. Acid phosphatases were increased at that age. Nevertheless, there were no abnormalities of staturoponderal milestones and no cognitive dysfunction. He went to school until the age of 16.
The patient was seen at the age of 26. He had difficulties in walking which progressively worsened and falls became frequent. He could, however, walk without aid and work as a clerk. He also complained of paroxystic dyspnoea. Neurological examination displayed a static and kinetic cerebellar syndrome associated with a tetrapyramidal syndrome. Falls were mainly due to paroxystic dystonic movements of the legs. Attacks of dyspnoea were also concommittant with paroxystic and abnormal contractions of the abdominal musculature which were considered of dystonic origin. The paroxystic manifestations were not as brisk as myoclonus and were actually reinforcements of abnormal dystonic postures which could be seen in both the arms and legs. Both dystonia and cerebellar syndrome were responsible for a dysarthria. A tremor of the head and of the arms was seen. There was an oculomotor paralysis. Voluntary movements were abolished in both vertical and horizontal gaze. The oculocephalic movements were, however, preserved, although at a very low speed and low amplitude, in the horizontal movements. The abdominal echography showed the absence of hepatomegaly, but the size of the spleen was increased (18.5 cm along its major axis). There were no radiographic bone abnormalities. Bone scintigraphy was also normal. Neuropsychological testing showed the following: Binois-Pichot test for cognitive capacities 91/100; Wechsler test for memory 80/100. There was a slowness of thought, but no significant defect. Behavioural abnormalities were noted with impulsivity and aggressivity. Clastic attacks were reported by his family. Brain MRI and EEG were normal. An ECG and cardiac echography were also normal. β Glucosidase2 was diminished in leucocytes (0.45 Units; normal 6.5–10.5 Units) and in cutaneous fibroblasts ( 23 Units; normal 80–370 Units). The haemogram was normal except for a thrombocytopenia with 71 000 cells /mm3. Acid phosphatases were increased (10.0 Units; normal 2.2–8.14 Units). Chitotriosidase when tested after 4 years of treatment, was still clearly increased (1012 Units; normal mean 20 Units).
The healthy parents, of Italian origin, were not consanguinous. They were tested for β glucosidase in leucocytes2; the concentrations were 4.1 Units for the father and 3.0 Units for the mother. The brother and sister refused testing.
Genomic DNA was analysed and partially sequenced. The patient gave informed consent according to bioethics in French Law and the Declaration of Helsinki. The presence of the L444P and D409H mutations was detected exactly as described in Boot et al.3 The Ncil restriction enzyme was used for the mutation L444P and the Styl restriction enzyme for the mutation D409H. The figure legend describes the way each mutation altered the restriction digest pattern.
The treatment was started at the age of 27 by the cerebroside β glucosidase of placental origin alglucerase (Ceredase, Genzyme, Cambridge, MA, USA), with 60 Units/kg body weight, by intravenous perfusion every 2 weeks until the age of 31. After this period, alglucerase was replaced by the recombinant enzyme imiglucerase (Cerezyme, Genzyme, Cambridge, MA, USA) and the patient has been treated up to the present (age 34) with the same posology and an identical time interval. Thus the patient has been treated for 8 years so far.
The propositus was heterozygous for the L444P and the D409H mutations. Sequencing showed that the patient did not have other point mutations. His father carried the L444P mutation and his mother the D409H mutation (figure). Informed consent was obtained for genetic studies.
The treatment was well tolerated. No antibodies against either form of the enzyme were found. The aesthenia rapidly disappeared. His spleen, still hypertrophied at the age of 28, was found to be normal (7.5 cm for the great axis) at the age of 31. The aggravation of the gait stopped. The ophtalmoplegia remained unchanged. The paroxystic dystonic manifestations disappeared. The tremor of the head and of the arms had also decreased in intensity. During this period, the only new medications were the substitutive enzymatic therapy and carbamazepine (600 mg/day). We are aware of the fact that the prescription of carbamazepine may in itself ameliorate paroxystic dystonic manifestations. No clastic attacks occurred after 2 years of the treatment. At the age of 34, neuropsychological evaluation was as follows: mini mental state examination score 25/30; Mattis scale for memory 23/25; Wisconsin test for verbal fluency: 2/6. Conceptualisation was correct for precise tasks. Brain MRI was still normal except for a slight cortical atrophy. There was a normal concentration of thrombocytes: 110 000/mm3 after 6 months and between 130–150 000/mm3 thereafter. Acid phosphatases tested at the age of 28 were normal (2.7 Units). The patient and his family noted a great improvement in his behaviour and dependency.
In infancy, this patient presented with the apparent type 2 acute neuronopathic form. Although death usually occurs by 2 years of age in the infantile form,4 this patient is still alive, and able to lead a nearly normal life with a professional activity. In type 3 Gaucher's disease, neurological signs develop between 6 and 15 years of age although there are some cases with earlier manifestations.
The number of mutations involved in Gaucher's disease is great.4 5 The L444P mutation is often associated with a more severe neurological manifestation. Patients carrying the L444P mutation and the D409H mutation have been reported to develop a form of type 3 Gaucher's disease in which the oculomotor signs are predominant and the visceral symptoms are discrete. This case differed significantly from these other cases.
In conclusion, the patient had a neurological form of Gaucher's disease and could be evaluated over 3 decades. Before enzyme substitutive therapy, the patient and his family reported a progressive deterioration of his neurological state. When he was treated, visceral and haematological symptomatology became normal; and there was a stabilisation or even a slight improvement of his neurological symptoms as well as modification of mood and behaviour, allowing a better integration in social life. Thus some patients with Gaucher's disease with early neuronopathic manifestation may have a benign course and profit considerably from enzyme supplementation.
We acknowledge Mrs Marri Verhoek for her skilful contribution. The follow up was performed in collaboration with the French Evaluation Committee for Treatment of Gaucher disease (CETG), who we also gratefully acknowledge. This work was possible through grant PHRC AOA 94033 from Assistance-publique-Hôpitaux de Paris, and grants from the lysosomal disease association VML and the Caisse Nationale de Prévoyance CNP.