A. Gelot

Perinatal-lethal Gaucher disease.

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom‐free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal‐lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non‐immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal‐lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35–43% of cases. Perinatal‐lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.

Cerebellar atrophy : an important feature of carbohydrate deficient glycoprotein syndrome type 1

Abstract We report three children, all younger than 2 years of age, presenting with cerebellar atrophy related to carbohydrate-deficient glycoprotein syndrome type 1, an autosomal recessive metabolic disease. One patient had multisystem disease; two others had mental retardation with ataxia. In all cases the cerebellar atrophy was diagnosed on magnetic resonance imaging and, in one case, confirmed by autopsy. The cerebellar atrophy predominantly affected the anterior lobe. Vertical orientation of the tentorium cerebelli from the neonatal period in two cases suggests antenatal onset of the disease. Biological tests confirmed the diagnosis in all cases.

Periventricular nodular heterotopia on prenatal ultrasound and magnetic resonance imaging

To describe the prenatal ultrasound and magnetic resonance imaging (MRI) findings suggestive of periventricular nodular heterotopia (PNH).

Abnormal shape of the cavum septi pellucidi: an indirect sign of partial agenesis of the corpus callosum

To describe and assess the presence of a new indirect sign of partial agenesis of the corpus callosum (pACC): an abnormally shaped cavum septi pellucidi (CSP).

Chapter 175 – Gaucher disease

Gaucher disease is an autosomal recessive condition due to glucocerebrosidase deficiency responsible for the lysosomal accumulation of glucosylceramide, a complex lipid derived from cell membranes, mainly in macrophages. It is due to mutations mostly in the GBA gene, although saposine C deficiency is due to mutations in the PSAP gene. It encompasses an extremely heterogeneous spectrum of clinical involvement from the fetus to adulthood. Splenomegaly, blood cytopenia, and bone involvement are the main manifestations of Gaucher disease, but nervous system degeneration is observed in about 5-10% of patients. The accumulation in neurons of glucosylceramide and its derivative, psychosine, are thought to underlie neuronal dysfunction and death, although Gaucher cells that mostly accumulate such substances are mainly macrophages. Enzyme replacement therapy dramatically improves the outcome of patients because of its extreme efficacy in the treatment of the systemic involvement. However, it has only limited effects on most neurological signs.

Early development of occipital horns in a classical Menkes patient.

ATP7A, the copper transporter ATPase gene responsible for Menkes disease, localized on Xq13.3, was cloned in 1993. The spectrum of clinical phenotypes linked to the ATP7A gene has expanded from classical Menkes disease (OMIM 309400) with neonatal onset and early death, encompassing rarer neonatal presentations with fractures and intracerebral hemorrhages to milder presentations of Menkes disease and the Occipital Horn syndrome (OHS, OMIM 304150) [Horn and et Tümer, 2002]. We present a classical Menkes patient with the first report, to our knowledge, of occipital horns on skull X-rays at 21⁄2 years of age. The boy, born in 1996, was the second child of healthy young non-consanguineous parents of Balkan origin. There was no family history of mental retardation or hair anomaly. The boy was delivered spontaneously at 38 weeks of gestation after an uneventful pregnancy. His birth weight was 3,690 g (90th centile), length 51 cm (90th centile), head circumference 35 cm (75th centile), Apgar 10/10. The neonatal period was unremarkable and hypotonia was not present. Psychomotoric milestones were normal until 8 months, when a regression was noted. When seen at 15 months, he was hypotrophic weighing 8 kg since 8 months of age (50th centile at 8 months, 3th centile at 15 months) and hypotonic, with persistence of head control, but loss of sitting ability. He had episodes of opisthotonos on stimulation. He had facial dysmorphism with occipital prominence and abnormal short, gray, and sparse hair. Head circumference had stagnated since 8 months, with acquired microcephaly. Myoclonic epilepsy appeared at 3 years. When last evaluated at 4 years 8 months, his weight was of 8.7 kg ( 1th centile,þ0.7 kg since 8 months of age), and head circumference was 47 cm, microcephalic (1st centile). There was no neurological progress, though he retained head control. The child was lost to follow-up at 5 years, terminally ill, presumed dying in his home country. R-banding chromosome analysis showed a normal 46, XY karyotype. Plasma copper was low (Table I), as was ceruloplasmin. Ophtalmological investigations showed optic disk pallor on fundus examination, visual evoked responses (VER), and electro-retinogram (ERG) were altered, revealing retinopathy state II. Hair microscopy showed pili torti. No metaphyseal flaring was found on X-rays, clavicles were not enlarged at 3 years of age. Skull radiography at 28 months showed wormian bones on lambdoid sutures, and budding occipital exostosis (Fig. 1). Magnetic resonance imaging (MRI) showed a dolichocephalic head, megavessels, with abnormal tortuosity (Fig. 2), a slight cerebral atrophy with mildly dilated ventricles. The copper incorporation into cultured fibroblasts confirmed the clinical diagnosis of Menkes disease. Copper uptake and retention values were both significantly increased: 141.5 ng copper per mg protein incorporated per 20-hr and 71.8% retained after the 24-hr efflux period. The ATP7A mutation of the patient was identified in exon 3, a private mutation, an 8 bp deletion (c.408_415delCAATCAGA, numbered according to the ATG start codon), which leads to a frameshift starting at amino acid 136, addition of 21 aberrant amino acids, and loss of the 1,363 amino acids long C-terminal sequence. RT-PCR performed on mRNA isolated from fibroblasts [Møller et al., 2000] did not identify any alternative transcripts. The mother did not carry the mutation. The term ‘‘occipital horn,’’ characteristic of OHS, refers to a wedge-shaped calcification that forms within the tendinous insertions of the trapezius and sterno-cleido-mastoid muscles at their attachment to the occipital bone. The cause of the tissue calcification is still uncertain, but may represent an inflammatory response to chronic injury of the involved tendons engendered by a combination of their reduced connective tissue strength from deficiency of lysyl-oxidase and their relationship to the powerful, frequently used muscle, trapezius, and sternocleido-mastoid [Kaler, 1998]. Deficit of the copper-dependent enzyme lysyl oxidase, secondary to the disturbed intracellular copper transport, is responsible for decrease of cross-links in elastin and collagen with resulting abnormal laxity of skin and connective tissues [Peltonen et al., 1983]. Presence of voluntary traction on these hyperlax tendons attached to the skull could then have provoked calcification of the occipital tendons, as an aberrant way of reparation. Early occipital horns reports stay rare in OHS, but have been found in retrospect in a few cases (Table I) [Herman et al., 1992; Proud et al., 1996; De Paepe et al., 1999]. Occipital horns have not been reported in classical Menkes patients. We suggest than occipital horns may appear in any ATP7A gene deleterious mutation, if voluntary traction on the trapezius and sterno-cleido-mastoid muscles persists after 2 years of age, needing both sustained voluntary head control (present in this case) and long survival *Correspondence to: M. Gérard-Blanluet, Génétique Médicale, Service de Néonatalogie, Centre Hospitalier Intercommunal de Créteil, 40 Avenue de Verdun, 94010 Créteil. E-mail: marion.gerard@chicreteil.fr

Prenatal features of isolated subependymal pseudocysts associated with adverse pregnancy outcome

To identify at prenatal ultrasound (US) the features of apparently isolated subependymal pseudocysts (SEPC) that may indicate underlying pathology and should lead to further investigations.

PROGRESSIVE MEGALENCEPHALY DUE TO SPECIFIC EIF2Bε MUTATIONS IN TWO UNRELATED FAMILIES

We report four patients, from two unrelated families, affected by an infantile form of childhood ataxia with central hypomyelination syndrome1 or vanishing white matter disease2 (CACH/VWM) with large megalencephaly in the three children with a protracted disease course. #### Patient 1. A girl, born in 1990 from unrelated parents, presented two acute episodes of neurologic deterioration during viral infections at ages 10 and 14 months, followed by a progressive decline. Brain MRI showed severe white matter abnormalities. At age 3, a cerebral biopsy was performed and was complicated by a subdural hematoma that did not explain the persistence of an excessive head growth (figure, A and B). Neuropathologic analysis showed an increased oligodendrocyte density but no Rosenthal fibers. Head circumference (HC) reached 58 cm, and she died at age 8.5. Figure Patients 1, 2, and 4 (A and B) Patient 1. Sixteen months after the cerebral biopsy, CT scan (A) shows a right subdural hematoma with collapse of the right hemisphere but without mass effect on the left hemisphere; the left hemispheric white matter appears severely hypodense with swelling and seems to compress the cortex; ventricles are slightly enlarged (arrowheads: ependymal lining). The head circumference (HC) curve shows an increased growth velocity after the age 2 (B) (arrow: …

Association of periventricular nodular heterotopia with posterior fossa cyst: a prenatal case series.

The association of periventricular nodular heterotopia (PVNH) with posterior fossa cyst (PFC) is documented after birth. We report this association in a series of fetuses.

Variability of T1-weighted signal intensity of pericallosal lipomas in the fetus

BackgroundPericallosal lipomas are often associated with corpus callosum dysgenesis. The diagnosis of lipoma, suggested on ultrasonography, relies on the classic T1 hyperintensity on magnetic resonance imaging (MRI). However, this feature may be absent prenatally.ObjectiveOur objective was to study the changes of T1 intensity in fetal lipomas with comparison to postnatal/postmortem data and to assess the factors influencing the signal variations of pericallosal lipomas on prenatal MRI.Materials and methodsPatients with callosum dysgenesis and interhemispheric hyperechogenicity suggestive of a pericallosal lipoma with available postnatal or postmortem data were included. Gestational age, lipoma size and pattern, corpus callosum size and changes in fetal fat T1 intensity were recorded. Comparison with postmortem neuropathology was available for one fetus.ResultsEleven patients with callosum dysgenesis and pericallosal lipomas (seven curvilinear and four tubulonodular) were included. All MRI scans were performed in the third trimester. Curvilinear lipomas were thinner and six cases were associated with prenatal T1 iso-intensity. Typical T1 hyperintensity appeared on postnatal MRI only. All tubulonodular lipomas were much larger and showed prenatal T1 hyperintensity. In two patients, the lipoma increased in size on postnatal MRI.ConclusionThe type and size of a lipoma influence T1 prenatal intensity. Absence of T1 intensity was observed in curvilinear lipomas only. Curvilinear lipomas are much thinner. Changes in T1 intensity may also be related to fat maturation within the lipoma and, subsequently, to gestational age. In the case of callosum dysgenesis, absence of prenatal T1 pericallosal hyperintensity should not exclude the diagnosis of pericallosal lipoma.