- Email: [email protected]
PP4.1 – 1595 X-linked adrenoleukodystrophy in childhood
E U R O P E A N JO U R N A L O F PAEDIATRIC N E U R O L O G Y
to cover all coding regions of the gene. Results: Paroxysmal dystonic features increased with age like other movement disorder symptoms including choreiform movements. Similarly to DYT12, dystonic features developed some signs of a rostrocaudal gradient (orofacial dystonia with dysphagia, dyspnoea). The mystery of AHC symptoms completely disappearing during sleep and reappearing again a few minutes after awakening, supports also movement disorder aetiology. ATP1A3 analysis revealed a pathogenic mutation c.2401G>A p. (Asp801Asn) in two patients, c.2839G>A p. (Gly947Arg) in one and 2839G>C p. (Gly947Arg) in another one. No mutation or deletion was detected in the last patient with atypical late onset of the disease. Conclusions: Our study suggests that AHC2 and DYT12 may represent a phenotypic continuum of one clinical entity, however, further genotype-phenotype studies are desirable to prove this hypothesis. AHC patients may represent the most severe type of ATP1A3associated dystonic movement disorder, while DYT12 patients would present only a mild variety of the same disease.
PP4. Neurometabolic disorders Chair: Rudy Van Coster PP4.0 - 1506 Longitudinal outcomes from the international disease registry for Niemann-Pick disease type C (NP-C) Pineda M, Mengel E, Wijburg FA, Vanier MT, Schwierin B, Muller A, Drevon H, Patterson MC. Fundació Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain – [email protected] Objective: This disease registry was initiated to evaluate the long-term disease course of NP-C in clinical practice. The current analysis focuses on patients who received miglustat continuously between enrolment and last follow up visit, based on data collected from September 2009 to August 2012. Methods: All patients diagnosed with NP-C, irrespective of treatment, were eligible for inclusion in this multicentre, prospective, observational cohort study. Patient demographics, disease characteristics, disability status and treatment data were collected. Disability status was evaluated using a disease-specific disability scale that rated four domains: ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Patients were categorised as “improved/stable” if ≥3 out of these 4 domain scores were lower or unchanged between enrolment and last follow-up visit, or as “worsened” if <3 domain scores were lower or unchanged. Results: Eighty out of the 190 enrolled patients (mean [SD] age at enrolment 17.8 [11.5] years; 52.5% female) received miglustat continuously throughout the observation period; mean (SD) exposure 1.19 (0.69) years. Among 74/80 patients with available data, the mean (SD) age at neurological onset was 9.9 (9.3) years. Ten (14%) patients had early-infantile onset (aged <2 years), 24 (32%) had late-infantile onset (2 to <6 years), 24 (32%) had juvenile onset (6 to <15 years), and 16 (22%) had adolescent/adult (≥15 years) onset of neurological manifestations. Mean (95%CI) composite disability scores at enrolment and last follow-up visit were 0.39 (0.34, 0.45; N=75) and 0.45 (0.39, 0.51; N=76), respectively. Overall, 52/72 (72%) patients were categorised as ’improved/stable’; 20/72 (28%) were categorised as “worsened”. Safety and tolerability findings were in line with previous published data. A low proportion of patients had chronic diarrhoea during follow up (7.6%). Conclusion: NP-C disease characteristics were in line with previous publications. Disability status was improved or stable in the majority of miglustat-treated patients.
17s (2013) S1 – S149
S39
PP4.1 - 1595 X-linked adrenoleukodystrophy in childhood Kim EY, Park JH, Kook H, Woo YJ. Department of Pediatrics, Kwangju Christian Hospital, Chonnam National University Medical School, Gwangju, Korea – [email protected] Purpose: X-linked adrenoleukodystrophy (ALD) is a rare disorder that shows a great deal of phenotypic variability. We subdivided chidhood X- linked ALD patients into several phenotypes by the age at onset, the sites of most severe clinical involvement and the rate of progression of neurologic symptoms. Methods: Fourteen patients who had been diagnosed as X- linked ALD and followed up for at least one year were enrolled from 1996 to 2010. Results: 1. Eleven had childhood cerebral ALD, who showed first neurologic symptoms at 7.29 years and progressed rapidly: interval between first symptoms and vegetative state was 1.48 years, and interval from initial symptoms to death was 3.44 years. Treatment with Lorenzo’s oil did not prevent neurologic progression. Two patients who underwent umbilical cord blood transplantation died. 2. Two had adolescent cerebral ALD. They had first symptoms at 11.5 years, and showed tendency to progress less rapidly than childhood cerebral form patients. 3. One “Addison only” patient who had adrenal insufficiency without nervous system involvement remained asymptomatic during Lorenzo’s oil treatment. 4. Most cerebral form patients except two showed the lesions in both parieto-ocipital white matter in brain magnetic resonance imaging. Conclusion: The cerebral ALD was the most common form in childhood and was asoociated with a grave prognosis.
PP4.2 - 1916 The clinical, biochemical and molecular characterisation of a UK patient with Salla disease. A case report Venkata NKP, Fry AE, van der Knaap MS, Scully R, Neal JW, Gibbon FM. Department of Paediatric Neurology, University Hospital of Wales, Cardiff, United Kingdom – [email protected] Salla disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the SLC17A5 gene. Salla disease (referring to the area of northeast of Finland where it was first described) has rarely been reported outside of Finland, where the p.R39C founder mutation leads to increased incidence. We report a UK patient with confirmed Salla disease. This male patient was the first child of non-consanguineous white British parents. He presented in infancy with speech and motor delay (sitting 1 year, walking 4 years). The patient subsequently developed ataxia, spastic paraparesis and generalised dystonia. At the age of 12 years he developed severe startle seizures and absences. The patient’s EEG was particularly abnormal with high amplitude spike wave discharges. He is now 14 years-old and can speak in simple sentences, finger feeds and dress with assistance. Repeated MRI brain scans showed almost complete absence of myelination of the cerebral white matter, reduced width of the cerebral mantle, thin corpus callosum and atrophic cerebellum. Cerebrospinal fluid analysis revealed an elevated level of N-acetylaspartylglutamate but sequencing of the PLP1 gene was normal. Thin layer chromatography of the patient’s urine demonstrated increased sialic acid excretion. Electron microscopy of a skin biopsy from the patient revealed Schwann cells containing intracytoplasmic inclusions. Cultured skin fibroblasts generated a 6 fold increase in free sialic acid. Sequencing of the SLC17A5 gene showed the patient was a compound heterozygote for two mutations: a previously-reported 5 amino-acid deletion (c.802_816del15; p.Ser268_Asn272del) and a novel missense mutation (c.116G>A, p.R39H). Analysis of maternal DNA confirmed that the changes were on different chromosomes. This case highlights Salla disease as a rare cause of leukodystrophy, which needs considered even in patients without a Finnish heritage.
to cover all coding regions of the gene. Results: Paroxysmal dystonic features increased with age like other movement disorder symptoms including choreiform movements. Similarly to DYT12, dystonic features developed some signs of a rostrocaudal gradient (orofacial dystonia with dysphagia, dyspnoea). The mystery of AHC symptoms completely disappearing during sleep and reappearing again a few minutes after awakening, supports also movement disorder aetiology. ATP1A3 analysis revealed a pathogenic mutation c.2401G>A p. (Asp801Asn) in two patients, c.2839G>A p. (Gly947Arg) in one and 2839G>C p. (Gly947Arg) in another one. No mutation or deletion was detected in the last patient with atypical late onset of the disease. Conclusions: Our study suggests that AHC2 and DYT12 may represent a phenotypic continuum of one clinical entity, however, further genotype-phenotype studies are desirable to prove this hypothesis. AHC patients may represent the most severe type of ATP1A3associated dystonic movement disorder, while DYT12 patients would present only a mild variety of the same disease.
PP4. Neurometabolic disorders Chair: Rudy Van Coster PP4.0 - 1506 Longitudinal outcomes from the international disease registry for Niemann-Pick disease type C (NP-C) Pineda M, Mengel E, Wijburg FA, Vanier MT, Schwierin B, Muller A, Drevon H, Patterson MC. Fundació Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain – [email protected] Objective: This disease registry was initiated to evaluate the long-term disease course of NP-C in clinical practice. The current analysis focuses on patients who received miglustat continuously between enrolment and last follow up visit, based on data collected from September 2009 to August 2012. Methods: All patients diagnosed with NP-C, irrespective of treatment, were eligible for inclusion in this multicentre, prospective, observational cohort study. Patient demographics, disease characteristics, disability status and treatment data were collected. Disability status was evaluated using a disease-specific disability scale that rated four domains: ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Patients were categorised as “improved/stable” if ≥3 out of these 4 domain scores were lower or unchanged between enrolment and last follow-up visit, or as “worsened” if <3 domain scores were lower or unchanged. Results: Eighty out of the 190 enrolled patients (mean [SD] age at enrolment 17.8 [11.5] years; 52.5% female) received miglustat continuously throughout the observation period; mean (SD) exposure 1.19 (0.69) years. Among 74/80 patients with available data, the mean (SD) age at neurological onset was 9.9 (9.3) years. Ten (14%) patients had early-infantile onset (aged <2 years), 24 (32%) had late-infantile onset (2 to <6 years), 24 (32%) had juvenile onset (6 to <15 years), and 16 (22%) had adolescent/adult (≥15 years) onset of neurological manifestations. Mean (95%CI) composite disability scores at enrolment and last follow-up visit were 0.39 (0.34, 0.45; N=75) and 0.45 (0.39, 0.51; N=76), respectively. Overall, 52/72 (72%) patients were categorised as ’improved/stable’; 20/72 (28%) were categorised as “worsened”. Safety and tolerability findings were in line with previous published data. A low proportion of patients had chronic diarrhoea during follow up (7.6%). Conclusion: NP-C disease characteristics were in line with previous publications. Disability status was improved or stable in the majority of miglustat-treated patients.
17s (2013) S1 – S149
S39
PP4.1 - 1595 X-linked adrenoleukodystrophy in childhood Kim EY, Park JH, Kook H, Woo YJ. Department of Pediatrics, Kwangju Christian Hospital, Chonnam National University Medical School, Gwangju, Korea – [email protected] Purpose: X-linked adrenoleukodystrophy (ALD) is a rare disorder that shows a great deal of phenotypic variability. We subdivided chidhood X- linked ALD patients into several phenotypes by the age at onset, the sites of most severe clinical involvement and the rate of progression of neurologic symptoms. Methods: Fourteen patients who had been diagnosed as X- linked ALD and followed up for at least one year were enrolled from 1996 to 2010. Results: 1. Eleven had childhood cerebral ALD, who showed first neurologic symptoms at 7.29 years and progressed rapidly: interval between first symptoms and vegetative state was 1.48 years, and interval from initial symptoms to death was 3.44 years. Treatment with Lorenzo’s oil did not prevent neurologic progression. Two patients who underwent umbilical cord blood transplantation died. 2. Two had adolescent cerebral ALD. They had first symptoms at 11.5 years, and showed tendency to progress less rapidly than childhood cerebral form patients. 3. One “Addison only” patient who had adrenal insufficiency without nervous system involvement remained asymptomatic during Lorenzo’s oil treatment. 4. Most cerebral form patients except two showed the lesions in both parieto-ocipital white matter in brain magnetic resonance imaging. Conclusion: The cerebral ALD was the most common form in childhood and was asoociated with a grave prognosis.
PP4.2 - 1916 The clinical, biochemical and molecular characterisation of a UK patient with Salla disease. A case report Venkata NKP, Fry AE, van der Knaap MS, Scully R, Neal JW, Gibbon FM. Department of Paediatric Neurology, University Hospital of Wales, Cardiff, United Kingdom – [email protected] Salla disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the SLC17A5 gene. Salla disease (referring to the area of northeast of Finland where it was first described) has rarely been reported outside of Finland, where the p.R39C founder mutation leads to increased incidence. We report a UK patient with confirmed Salla disease. This male patient was the first child of non-consanguineous white British parents. He presented in infancy with speech and motor delay (sitting 1 year, walking 4 years). The patient subsequently developed ataxia, spastic paraparesis and generalised dystonia. At the age of 12 years he developed severe startle seizures and absences. The patient’s EEG was particularly abnormal with high amplitude spike wave discharges. He is now 14 years-old and can speak in simple sentences, finger feeds and dress with assistance. Repeated MRI brain scans showed almost complete absence of myelination of the cerebral white matter, reduced width of the cerebral mantle, thin corpus callosum and atrophic cerebellum. Cerebrospinal fluid analysis revealed an elevated level of N-acetylaspartylglutamate but sequencing of the PLP1 gene was normal. Thin layer chromatography of the patient’s urine demonstrated increased sialic acid excretion. Electron microscopy of a skin biopsy from the patient revealed Schwann cells containing intracytoplasmic inclusions. Cultured skin fibroblasts generated a 6 fold increase in free sialic acid. Sequencing of the SLC17A5 gene showed the patient was a compound heterozygote for two mutations: a previously-reported 5 amino-acid deletion (c.802_816del15; p.Ser268_Asn272del) and a novel missense mutation (c.116G>A, p.R39H). Analysis of maternal DNA confirmed that the changes were on different chromosomes. This case highlights Salla disease as a rare cause of leukodystrophy, which needs considered even in patients without a Finnish heritage.