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

Abstract

SUMMARY 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. OPCA is combined with systemic and biochemical abnormalities. Case reportsCase I was the first child of unrelated Caucasian parents. She was born at term, by normal delivery, weighing 2-8 kg. Apgar scores were satisfactory but after 48 hours she was transferred to the special care baby unit with lethargy, hypothermia and feeding problems. Clinical suspicions of septicaemia were not confirmed by screening but she continued to show failure to thrive. There was obvious oedema of the lower limbs and hepatomegaly, and a pericardial effusion was detected by 2D-Echo when she was 5 weeks old. Weight gain remained poor, diarrhoea was an additional problem, and protein losing enteropathy was suspected. She required several plasma transfusions because of oedema. There was also concern about her vision, when roving eye movements were observed. At the age of 6 months, she was transferred to the Hospital for Sick Children, for investigation of her failure to thrive. Her weight was 3-3 kg, length 55 cm, head circumference 38-5 cm; all measurements were well below the 3rd centile. She was slow to feed, wasted, lethargic, generally hypotonic and developmentally retarded. There were no dysmorphic features. She had occasional roving nystagmoid eye movements, but fixed well and could follow light. Ophthalmoscopic examination showed pale but not hypoplastic discs and pale fundi, diagnosed as retinal dystrophy. The liver edge was palpable 2-3 cm below the costal margin. Limitation of hip abduction was also noted.Chest radiographs confirmed the presence of a small pericardial effusion, and abdominal ultrasound demonstrated hepatomegaly and ascites. The EEG was normal. The ERGs had abnormally small amplitude and unusual waveforms, 385 by copyright.

Prenatal diagnosis of fatal infantile olivopontocerebellar hypoplasia syndrome

“…There is debate as to whether these diseases represent an acquired loss of neural tissue or are the result of a primary failure of normal embryological development of the affected structures. Although there has been a case report of OPCH in an infant with in utero phenytoin exposure (Gadisseux et al, 1984) most cases have been postulated to be hereditary (Colan et al, 1981;Lutz et al, 1989;Albrecht et al, 1993;Harding et al, 1988;Kristiansson et al, 1989;Horslen et al, 1991;Chang et al, 1993;Bawle et al, 1995). In our patient, no history of any potential teratogens could be elicited and she did not have any systemic medical disease.…”

“…These infants present with failure to thrive, generalized hypotonia, areflexia, liver dysfunction, poor sucking reflex, feeding difficulties and dysmorphic features. This disease demonstrates an autosomal recessive pattern of inheritance (Harding et al, 1988;Kristiansson et al, 1989;Horslen et al, 1991;Chang et al, 1993;Bawle et al, 1995) and the diagnosis is confirmed by demonstrating abnormal glycosylation of serum glycoproteins by serum electrophoresis. We did not test for CDGI since the clinical presentations of these two siblings were not consistent with this diagnosis.…”

“…Infantile forms of OPCH/OPCA are very rare. A review of the literature suggests that many cases with onset in the neonatal period or in the first few months of life tend to have a more rapidly progressive deterioration, and death usually occurs within months to a few years (Harding et al, 1988;Horslen et al, 1991;Bawles et al, 1995;Albrecht et al, 1993). Most cases appear to exhibit an autosomal recessive mode of inheritance.…”

Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate‐deficient glycoprotein syndrome

“…Olivopontocerebellar atrophy of neonatal onset, a multisystem disorder with very characteristic neuropathology, was described by Agamanolis et al in 1986 andHarding et at in 1988. Recently we were able to show that, as predicted by Jaeken (1989), this disorder is associated with carbohydrate-deficient gtycoproteins and thus represents the most severe end of the spectrum of diseases recently reviewed by Jaecken et al (1991).…”

Pontocerebellar hypoplasia type 1

“…Abnormal oculomotor function (strabismus, nystagmus, oculomotor apraxia) was commonly observed in patients surviving beyond infancy. Additional organ involvement such as gonadal dysgenesis, 16 also seen in patient 23-2 (table e-2 8 ), retinal degeneration or optic nerve atrophy, 5 hepatic fibrosis, and cystic kidney disease 17 are also not yet reported in patients with EXOSC3 mutations. Mesangiocapillary glomeronephritis was diagnosed in a mutation-positive Australian patient 6 (patient 4 in reference 18).…”