Myoclonus in fraternal twin toddlers: A French family with a novel mutation in the SGCE gene

Myoclonus dystonia is a rare movement disorder caused by mutations in the SGCE gene on chromosome 7q21 (DYT11) encoding the epsilon-sarcoglycan. Myoclonus is present in almost all patients and affects most often neck, trunk and upper limbs. Dystonia is present in about half of the patients. The mode of inheritance is autosomal dominant with variable clinical expression and maternal imprinting. Onset is usually in childhood or adolescence. Alcohol might relieve symptoms.We present a 33 month old girl and her twin brother with disabling involuntary jerky movements during intentional tasks. Family history of this French family was positive for the paternal uncle, his two daughters and the paternal great grandfather. Sequencing of the SGCE gene revealed a novel nonsense mutation c.942C > A (p.Tyr314X) in exon 7, confirming the diagnosis of myoclonus dystonia. Treatment with valproic acid significantly reduced myoclonic episodes and ameliorated life quality.     

Pediatric writer's cramp in myoclonus-dystonia: Maternal imprinting hides positive family history

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder with myoclonic jerks and dystonic contractions most frequently due to a mutation in the ?-sarcoglycan (SGCE, DYT11) gene. We describe two unrelated children with M-D (DYT11) who presented with writer's cramp. Due to maternal imprinting the family history appeared initially negative for M-D. In children with writer's cramp screening of the SGCE gene should be considered, even with a negative family history.     

A novel SGCE gene mutation causing myoclonus dystonia in a family with an unusual phenotype

Background: Myoclonus dystonia is an autosomal dominant dystonia‐plus syndrome, characterized by symptom variability within families. Most often is the myoclonus the most debilitating symptom, and many patients report myoclonus reduction after alcohol intake. In several families, mutations in the SGCE gene have been identified. Method: We report of a three‐generation family with myoclonus dystonia displaying a varied phenotype and maternal imprinting. Additionally, this family displays some unusual clinical presentations including alcohol‐induced dystonia in an adult man, which will be discussed. Results: A novel mutation c.386T>C [p.I129T] was found within exon 3 of the SGCE gene in all three affected family members. In addition, two additional mutations [c.305G>A and IVS3+15G>A], judged to be polymorphisms in the SGCE gene, were found in two affected and one healthy family member. Conclusions: This report presents a novel mutation in the SGCE gene causing myoclonus dystonia and extends the phenotype of myoclonus dystonia to also include alcohol‐induced dystonia.     

Continuous intrathecal baclofen for children with spasticity and/or dystonia: Goal attainment and complications associated with treatment

Aim: To describe complications and outcomes of intrathecal baclofen (ITB) therapy in children with spasticity and/or dystonia. Methods: A prospective study of goal attainment after ITB therapy and a retrospective review of medical records for complications. The children were described as dystonia‐predominant or spasticity‐predominant and the subgroups were compared. Goals were assessed at baseline and goal attainment at 6 months post‐implant. Data were analysed using Wilcoxon signed‐rank test. The patients' goals were measured with the Canadian Occupational Performance Measure (COPM) and goal attainment scaling (GAS). Complication rates were calculated by dividing the number of complications by the duration of pump implantation. Results: Twenty‐five children were included, 16 with complete goal attainment data. The mean age was 10 years and 3 months. Eighty‐eight percent had a diagnosis of cerebral palsy. The most common goals were improved positioning and transfers. A statistically significant increase (P < 0.001) in both domains of the COPM was demonstrated. The mean GAS T‐score was significantly higher at 6 months post implant (P < 0.001). Seventy percent of the subjects achieved their goals at 6 months. The complication rate was 0.38 per year of pump operation, higher in subjects with dystonia (0.71) compared with those with spasticity (0.25). Conclusions: ITB results in statistically significant levels of satisfaction and goal attainment in children with spasticity and/or dystonia. GAS was a useful measure of goal attainment. While, ITB is effective for children with spasticity and dystonia, those with dystonia have a higher rate of complications.     

Polymyography in the diagnosis of childhood onset movement disorders

We report on the results of a clinical and polymyographic retrospective study of 61 paediatric patients with tremor, dystonia and/or myoclonus. Aim of the study was to verify the contribution of polymyography in the classification of these movement disorders and in their aetiological definition.

Methods

The movement disorders were clinically classified by two experts, based on clinical and videotape recordings evaluation; all patients underwent standardized polymyographic evaluation; aetiological diagnosis was performed according to diagnostic protocols for dystonia, myoclonus, tremor and psychogenic movement disorders. The polymyographic features were summarized in five different patterns (dystonia, subcortical myoclonus, myoclonic dystonia, tremor, normal) and compared with the clinical classification and with aetiological diagnosis.

Results

In more than 70% of the patients the polymyographic features were in accordance with the clinical classification; in 31% the polymyographic features allowed to identify a clinically unclassified movement disorder and in 19.6% disclosed a not clinically evident associated movement disorder. The polymyographic study did not contribute to the aetiological diagnosis, but was useful in supporting the clinical diagnosis of psychogenic movement disorder.     

Early myoclonic epilepsy,hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2)

BackgroundPrimary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life.MethodsAn infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage.ResultsAt three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2.ConclusionsIn contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.     

Development of smooth pursuit eye movements in very prematurely born infants: 2. The low-risk subgroup

Aim: To investigate the impact of premature birth on visual tracking in a group of 37 infants, born before the 32nd gestational weeks (mean 29 + 6 weeks) and diagnosed as being without major neonatal complications. This paper is a part of the LOVIS study (Strand Brodd, Ewald, Grönqvist, Holmström, Strömberg, Von Hofsten, et al. Acta Pediatrica, 2011). Methods: At 2 and 4 months corrected age, eye and head movements were measured when the infant tracked a moving object. The eye movements were analysed in terms of smooth pursuit and saccades (Vision Res, 37, 1997, 1799; Exp Brain Res, 146, 2002, 257). Accuracy of gaze, proportion of smooth pursuit, head movements and saccades were calculated. Results: Between 2 and 4 months of age, all infants improved their ability to smoothly pursue a moving object. However, at both occasions, the preterm infants had less proportion smooth pursuit than the full‐term infants. The groups did not differ with respect to gaze and head movements, but the saccade frequency was higher for the very preterms in some of the conditions. Conclusion: The development of smooth pursuit in the low‐risk preterm infant group was strongly delayed compared to typically developed infants. Thus, the 2 months or more extra visual experience did not have a distinguishable positive effect on visuo‐motor development as expressed in smooth pursuit.     

GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.     

Combined heterotopic liver–pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis

Cystic fibrosis (CF) is an inherited disease with a defect in epithelial chloride transport that results in a multisystem disease. Although pulmonary disease remains the primary cause of morbidity and mortality, focal biliary cirrhosis and portal hypertension may develop in up to 8% of these patients. Liver transplantation (TX) is an accepted therapy and shows good results. We report on a patient with cystic fibrosis homozygous for the most common CFTR mutation delta F 508 who received a combined heterotopic liver and pancreas transplantation at the age of 18 yr. He suffered from CFRD, which untypically required high doses of insulin. In addition, the patient had pulmonary complications, was chronically colonized with multiresistant Pseudomonas aeruginosa (MBL) and had an allergic bronchopulmonary aspergillosis (ABPA). The patient remained in stable health for 54 months post‐TX and was able to live a nearly normal life. With a follow‐up of five yr, the function of the liver and pancreas allografts was excellent. However, and sadly, his pulmonary function continued to deteriorate from progression of his CF, and he died of respiratory failure due to a severe pneumonia and septicemia at the age of 23 yr and five months.     

Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation

MIRAGE syndrome caused by mutations in SAMD9 is associated with potential loss of chromosome 7 (‐7/7q‐) and an increased risk to develop myelodysplastic syndrome (MDS). We report a case of MIRAGE syndrome, caused by a novel SAMD9 mutation p.Leu641Pro, leading to characteristic clinical features as well as to the coexistence of cells with monosomy 7 (20%) and with uniparental disomy of long arm of chromosome 7 (UPD7q). In contrast to previously reported MIRAGE patients with ‐7/7q‐ developing MDS, our patient achieved complete cytogenetic remission of monosomy 7. As UPD7q remained unchanged, it seems to be a protective factor against MDS.     

Early onset primary dystonia

Dystonia is a syndrome characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. It is classified by age at onset, by distribution, and by aetiology. The aetiological classification distinguishes the following categories: primary, dystonia plus, secondary, heredo-degenerative and psychogenic dystonia.Primary dystonia is defined as clinical condition characterized by dystonia as the only neurological abnormality apart from tremor. Different genetic alterations and gene loci have been mapped in familial and sporadic patients. Early onset-primary dystonia (EO-PD) is the most severe form of primary dystonia, with clinical and genetic heterogeneity. It usually starts in one body part, subsequently spreads to involve other body regions with frequent generalization. DYT1 dystonia is transmitted as an autosomal dominant trait with reduced penetrance. The unique underlying mutation is a GAG deletion in the coding region of the TOR1A gene, located at chromosome 9q34. DYT16 dystonia is a novel recessive form of EO-PD, recently described in few patients, caused by mutations in the PRKRA gene located at chromosome 2q31. At least other two loci have been mapped, but there remains a large number of patients with EO-PD in whom no genetic alteration is discovered.     

VPA-induced recurrent pancreatitis in a cystic fibrosis carrier

A 4.5 years old male with myoclonic epilepsy on Valproic acid (VPA) monotherapy, developed an acute pancreatitis. The discontinuation of VPA and substitution with Levetiracetam was followed by clinical improvement but a relapse of the pancreatitis was noted one month later. The investigation excluded a structural abnormality but revealed a heterozygous CTFR mutation. The contribution of the CTFR mutation on this VPA-induced recurrent pancreatitis cannot be ignored.     

Permanent neonatal diabetes in siblings with novel C109Y INS mutation transmitted by an unaffected parent with somatic mosaicism

Mutations involving the insulin (INS) gene are a common cause of permanent neonatal diabetes (PND). Although INS mutations typically occur de novo and germline INS mutations transmitted to offspring by unaffected parents has been described, somatic mosaicism in a parent with an INS mutation has not been previously reported. We describe two siblings (one brother and one sister) with PND (26‐ and 19‐yr old diagnosed at 3 and 7 months old, respectively), whose parents were unaffected. We performed genetic analysis of leukocyte DNA for this family. Both patients were found to carry the novel heterozygous c.326G>A substitution in exon 3 of INS, resulting in a p.C109Y change of the insulin protein. Analyses of leukocyte DNA from the parents revealed low level mutation in the sequencing trace of the father, raising the possibility of somatic mosaicism. Real‐time polymerase chain reaction (PCR) analysis showed he had approximately 73% of the mutant allele relative to his affected son. This first report of somatic mosaicism in an unaffected parent with an INS mutation suggests that parental mosaicism may be responsible for the transmission of PND in patients with de novo INS mutations. As such, appropriate counseling for recurrent risks should be considered and we recommend that molecular genetic testing for future siblings at birth should be offered to the parents of children with INS mutation.     

Acute lymphoblastic leukemia after temozolomide treatment for anaplastic astrocytoma in a child with a germline TP53 mutation

We present a case of a 12‐year‐old female with a germline TP53 mutation who presented with anaplastic astrocytoma and subsequent acute lymphoblastic leukemia (ALL) 13 months after starting treatment with temozolomide (TMZ). The patient had no family history of malignancy except her grand father and his siblings. Although alkylating agents such as TMZ are known to induce secondary hematologic malignancy, only several cases of treatment‐related acute leukemia have been reported after TMZ‐alone chemotherapy for malignant gliomas. We demonstrate a rare case of TMZ‐related ALL in a child with glioma possibly associated with a germline TP53 mutation. Pediatr Blood Cancer. 2010;55:577–579. © 2010 Wiley‐Liss, Inc.     

Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13‐year‐old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non‐classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3‐year follow‐up, he had stable disease. Pediatr Blood Cancer 2010;54:473–475. © 2009 Wiley‐Liss, Inc.     

A Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome with a KAT6B 10‐base pair palindromic duplication: A recurrent mutation causing a severe phenotype mixed with genitopatellar syndrome

The Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome (SBBYSS) (MIM# 603736) and genitopatellar syndrome (GPS) (MIM#606170) are allelic diseases caused by KAT6B mutation. Genotype–phenotype correlation is assumed, but a few patients manifest overlapping features of both syndromes. Here we report the case of a boy with SBBYSS. He had a KAT6B mutation previously reported in typical SBBYSS, but he also manifested severe developmental delay, as well as genital features and laryngomalacia requiring tracheostomy that conformed to GPS.     

Necessary stem cell transplantation using myeloablative therapy for myelodysplastic syndrome with progression of genotypic abnormalities and TP53 dysfunction in a young adult

A 14‐yr‐old male was admitted to our hospital with MDS and the chromosomal abnormality 45,XY,der(5;17)(p10;q10). He rapidly developed karyotype abnormalities, accompanied by the loss of tumor suppressor gene TP53 function. He suffered an early relapse after reduced‐intensity‐conditioning SCT and ultimately required myeloablative therapy before a second SCT. We consider that the analysis of TP53 mutations is essential when planning the treatment of patients with MDS.     

Hyperphenylalaninemia due to impaired dihydrobiopterin biosynthesis

A fourteen month-old boy with atypical phenylketonuria was treated with 5-hydroxytryptophan, L-dopa and peripheral aromatic amino acid decarboxylase inhibitor (Ro 4-4602:benserazide). Despite the good control of plasma phenylalanine on a low phenylalanine diet, he had shown no improvement in his development but progressive neurological symptoms, such asiirritability, convulsions and decrease voluntary movement. After beginning neurotransmitter therapy, his irritability disappeared promptly and the other symptoms diminished. He gradually reached his developmental milestones. At two and a half years of age, he had recovered sufficiently to be able to walk freely on treatment with 13 mg/kg/day of 5-hydroxytryptophan, 11 mg/kg/day of L-dopa and 2.7 mg/kg/day of benserazide in combination with slight restriction of phenylalanine intake (100 mg/kg/day).Levels of serotonin and 5-hydroxyindoleacetic acid were low in the patient's CSF. His urinary biopterin (Crithidia factor) excretion was low. An increase in serum biopterin following L-phenylalanine loading was not found. Dihydropteridine reductase activity in his skin fibroblasts was normal. He excreated large amounts of erythro- and threo-neopterins (but only a trace of biopterin) in his urine. After loading with phenylalanine the urinary excretion of neopterins was even more enhanced, but biopterin remained at low levels. These findings indicated that the patient has a dihydrobiopterin synthetase deficiency.     

Effect of clonidine on the height of a child with glycogen storage disease type VI: A 13 year follow-up study

A 9-month-old male was found to have hepatomegaly when he was treated by his doctor for bronchitis. At the age of 2 years and 3 months, glycogen storage disease (GSD) of type VI (GSD VI) was diagnosed in this patient. Despite the recommended diet therapy, his growth was not good, changing under or along the line of ?2.0 SD. At the age of 6 years, oral clonidine therapy (0.15 mg/day, 0.2 mg/m² body surface per day) was started. Six to 10 months after the initiation of clonidine therapy, his height began to increase more than the values for ?2.0 SD and once reached the value for ?1.0 SD at the age of 10 years. His growth rate and bone age increased. Clonidine therapy was continued regularly for 7 years until the age of 13 years, 11 months. At that time his development was normal and his height reached 150.8 cm (–1.34 SD). However, cessation of the treatment at the patient's free will resulted in a reduction of the growth rate at age 15 years 6 months. These observations suggest the effect of clonidine therapy on height. Side effects were not noted during the clonidine therapy. Other clinical and laboratory findings of GSD VI also completely improved during treatment. In conclusion, administration of clonidine could be another treatment modality in children with GSD, not only of type VI but also I and III.     

A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5

Dent disease is an X-linked tubulopathy mainly caused by inactivating mutations of CLCN5. Features of Bartter syndrome such as hypokalemic metabolic alkalosis are rarely observed in patients with Dent disease. We report a Japanese male patient with Dent disease who also manifested features of Bartter syndrome. At the age of 3 years, he was diagnosed with Dent disease based on low molecular weight proteinuria and hypercalciuria. One year later, he was found to have features of Bartter syndrome, i.e., hypokalemia and metabolic alkalosis, and high levels of plasma renin activity and aldosterone with a normal blood pressure. Despite medical interventions, he developed chronic kidney disease stage 3 at the age of 21 years. To investigate the molecular basis of his disease, CLCN5, KCNJ1, SLC12A1, and CLCkb were analyzed and a novel mutation (Y567X) in CLCN5 was identified. Conclusion: Hypokalemic metabolic alkalosis is a rare manifestation in Dent disease. It is speculated that Dent patients with features of Bartter syndrome are susceptible to progression to renal failure. To study this hypothesis, additional observations and long-term follow-up of such patients are necessary.