Cerebrotendinous xanthomatosis without neurological involvement.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. METHODS: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. RESULTS: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. CONCLUSIONS: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome.

Myotonic dystrophy type 2 (DM2) is a rare, autosomal dominant, multisystem disorder with proximal weakness, myotonia, pain and cataract as important symptoms. Given the assumed underreporting of DM2 in the Netherlands combined with the predominant role of pain in DM2 as well as in fibromyalgia syndrome (FMS), we hypothesized there will be an excess prevalence of DM2 in patients with (suspected) FMS. Our objective was to determine the prevalence of DM2 in patients with suspected FMS. A prevalence of 2% was considered a relevant excess frequency. Between November 2011 and April 2014, 398 patients with suspected FMS who had been assessed by a rheumatologist participated in this cross-sectional study. 95% of the study population was female, with a mean age of 42 years. The final ICD-9 diagnoses were collected, in 96% the diagnosis was FMS. 92% met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FMS. A questionnaire including neuromuscular symptoms was completed. Creatine kinase was determined, and genetic testing for DM2 was conducted in all patients. DM2 was established in only one patient (0.25%, 95% CI 0.04-1.4%), thus disapproving our hypothesis of a relevant prevalence of 2%. Our results suggest that patients with suspected FMS should not routinely be tested for DM2.

Severe hypomagnesaemia causing reversible cerebellopathy.

Hypomagnesaemia is common among hospitalised patients and is often under-recognised. Chronic alcohol abuse and alcohol withdrawal are known causes for severe hypomagnesaemia. Hypomagnesaemia can present with cardiac arrhythmias, seizures and other neurological symptoms, among which ataxia. We present a 57-year-old man with a history of chronic alcohol abuse who developed a subacute cerebellar syndrome with hypertension after alcohol withdrawal. A severe hypomagnesaemia of 0.19 mmol/L (normal values 0.70-1.10) was found. MRI showed diffuse, T2 hyperintense lesions in and swelling of the cerebellum. Symptoms, hypertension and MRI abnormalities significantly improved rapidly after intravenous magnesium supplementation. Hypomagnesaemia can cause a subacute, cerebellar syndrome and hypertension. Symptoms, hypertension and MRI abnormalities can be reversed with rapid magnesium supplementation. MRI abnormalities are similar to those caused by vascular endothelial dysregulation seen in posterior reversible encephalopathy syndrome (PRES). A similar case was recently described. We confirm that magnesium is likely to be involved in the pathophysiology of PRES.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

A previously healthy 11-year-old girl with behavioural disturbances, desquamation of the skin and loss of teeth.

An 11-year-old girl was admitted with backpain, weight loss, fatigue and behavioural disturbances, starting seven weeks before admission. Physical examination showed acrodynia, tremor, cachexia, hypertension and extensive gingival ulceration. Routine laboratory tests were normal, except for a CRP of 98 mg/l. Screening tests for recreational drugs as well as antibody assays for HIV, hepatitis B and borrelia burgdorferia were negative. Chest X-ray, brain CAT and MRI scan were all normal. Lumbar puncture didn't show any abnormalities. Eventually a 24-hour urine test confirmed the diagnosis that was suspected by further questioning.

Postural headache in marfan syndrome associated with spinal cysts and liquor hypotension.

We here report a 13-year-old Marfan patient who suffered from severe, medication-resistant, intermittent headache, which was provoked when getting into an upright position and immediately relieved by lying down or after intravenous rehydration. The postural benefit and the sudden relief after intravenous hydration suggested (intermittent) intracranial hypotension, although a normal opening pressure on lumbar punction was observed and no cerebrospinal fluid (CSF) leakage was identified. Imaging studies revealed severe dural ectasia at lumbosacral level, and two intradural cysts and two extradural presacral cysts were detected. Most likely, altered hydrodynamics in intra- and extracranial spinal meningeal cysts caused intermittent CSF hypotension above these cysts, resulting in intermittent intracranial hypotension. Surgical marsupialisation of the intradural cysts proved to be effective. This resulted in a significant reduction of the headache during the clinical follow-up of eight years.

Elevated cholesterol precursors other than cholestanol can also be a hallmark for CTX.

Cerebrotendinous xanthomatosis (CTX) is an inborn error of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids is impaired. Patients have abnormal bile alcohols in urine, normal to increased plasma cholesterol concentrations and increased concentrations of plasma cholestanol. Little is known about cholesterol precursors in CTX, however. We studied cholesterol and phytosterol profiles in two siblings with CTX during follow-up. While cholesterol concentrations were low in both patients, plasma cholestanol was 6-fold higher compared to control values. In addition, both siblings had a more than 100-fold increase in 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC). Lathosterol, lanosterol and sitosterol were increased in both patients while concentrations of desmosterol and campesterol were normal. In addition, plasma lathosterol/cholesterol ratios were significantly elevated. After treatment with chenodeoxycholate, both patients showed a marked decrease in cholestanol, 7DHC, 8DHC, lathosterol, lanosterol and sitosterol. In addition, the lathosterol/cholesterol ratio normalized, indicating that overall cholesterol synthesis was sufficiently suppressed. This study shows that elevated cholesterol precursors, other than cholestanol, can be a hallmark for CTX.

Prognostic factors after a first attack of inflammatory CNS demyelination in children.

OBJECTIVE: To identify clinical, radiologic, or CSF factors that predict conversion to multiple sclerosis (MS) after a first attack of inflammatory demyelination in children. METHODS: In this nationwide retrospective multicenter study in the Netherlands, 117 children below age 16 were included. Fifty-four children presented with a monofocal clinically isolated syndrome (CIS) and 63 children with a polyfocal CIS (PCIS). RESULTS: A second MS-defining attack occurred in 43% of the CIS cases, compared to 21% of the patients with PCIS onset (p < 0.006). Basal ganglia and thalamic lesions and lesions larger than 2 cm on MRI (considered typical of ADEM) were observed during PCIS, irrespective of the presence of encephalopathy. No significant difference in developing MS was found in children with PCIS with or without encephalopathy. Elevated IgG index and presence of oligoclonal CSF bands were more often observed in children who developed MS. Both Barkhof and KIDMUS MRI criteria shared a high specificity and had a high positive predictive value for conversion to MS. In children under the age of 10, the Barkhof criteria had a higher sensitivity than the KIDMUS criteria, but still lower than in older children. CONCLUSIONS: Barkhof and KIDMUS MRI criteria share a high specificity and positive prognostic value for conversion to multiple sclerosis (MS). Sensitivity of these criteria is poor, especially in children below 10 years of age. Basal ganglia lesions can occur in patients who later develop MS. A substantial number of patients presenting with polyfocal onset and no encephalopathy remained monophasic.

Quantitative skeletal muscle ultrasound: diagnostic value in childhood neuromuscular disease.

UNLABELLED: In this study we investigated the diagnostic value of quantitative skeletal muscle ultrasonography in 150 consecutively referred children with symptoms suspect for a neuromuscular disorder. Muscle thickness and quantitatively determined echo intensity of four muscles and the distribution of these variables within the body were examined. RESULTS: Patients with and without a neuromuscular disorder could be discriminated with a positive predictive value of 91% and a negative predictive value of 86%. Patients with a neurogenic disorder could be distinguished from myopathies and non-neuromuscular disorders with a positive predictive value of 86% and a negative predictive of 84%, using the pattern of distribution of pathology within the body. CONCLUSIONS: Skeletal muscle ultrasound is a good, practical and non-invasive aid in the diagnosis of neuromuscular disorders in children, that is able to discriminate between children with and without a neuromuscular disorder and between neurogenic disorders and myopathies with high predictive values.

Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome.

BACKGROUND: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of alpha-dystroglycan (alpha-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. OBJECTIVE: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. METHODS: A candidate gene approach combined with homozygosity mapping. RESULTS: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated alpha-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. CONCLUSIONS: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of alpha-DG.

Hypovitaminosis D-related myopathy in immigrant teenagers.

INTRODUCTION: Vitamin D deficiency resulting in a limb-girdle muscle weakness was diagnosed in three veiled immigrant teenage girls. PATIENTS: Three girls had a progressive muscle weakness and pain during a period varying from 6 months to two years. On examination limb girdle muscle weakness, predominantly of the lower extremities, without other neurological abnormalities was found. Serum examination showed a decreased level of vitamin D and phosphate and an increased alkaline phosphatase, and in two girls decreased calcium and increased parathyroid hormone levels were found. After supplementation with vitamin D, the pain subsided and muscle strength increased within weeks. Serum examination of the female relatives revealed eight persons with hypovitaminosis D, without any complaints. CONCLUSIONS: Vitamin D deficiency can result in a limb-girdle myopathy in veiled immigrant teenagers in the Netherlands. Vitamin D supplementation leads to rapid recovery of the muscle strength. The female relatives of these patients should be examined too.

Quantitative ultrasonography of skeletal muscles in children: normal values.

The purpose of this study was to establish normal values of muscle thickness, ratio of muscle thickness to subcutaneous fat thickness, and muscle echo intensity in children between 11 weeks and 16 years of age. Transverse scans of four muscles were made by standardized real-time ultrasound examination. The scans were digitized, and mean echo intensity was measured using gray-scale analysis. A multiple regression equation was used to study which independent parameter (age, height, weight, or sex) influenced the variables for each muscle. Muscle thickness depended on the child's weight. The other parameters did not significantly influence muscle thickness after correction for weight. The ratio of muscle thickness to subcutaneous fat thickness depended on age. Echo intensity showed no correlation with either of the variables. As a result, all normal values, including the equation to calculate them, are described. These normal data may help to determine the diagnostic value of muscle ultrasound in children with suspected neuromuscular disease.

Quantitative skeletal muscle ultrasonography in children with suspected neuromuscular disease.

We determined prospectively the diagnostic value of quantitative ultrasonography in detecting neuromuscular disorders in children. Ultrasonographic scans of four muscles were made in 36 children with symptoms or signs suggestive of neuromuscular disease, such as muscle weakness and hypotonia. The muscle thickness, ratio of muscle thickness to subcutaneous fat thickness, and echo intensity were determined in each muscle. The echo intensity was measured using computer-assisted gray-scale analysis. Thirteen of the 36 patients had a neuromuscular disorder (6 a myopathy and 7 a neuropathy). Differentiation between neuromuscular diseases and nonneuromuscular diseases could be made on the basis of echo intensities with a sensitivity of 92%, a specificity of 90%, a positive predictive value of 86%, and a negative predictive value of 95%. We conclude that computer-assisted quantitative analysis of muscle echo intensity is a reliable method to discriminate between neuromuscular and nonneuromuscular diseases in children.

[Amyoplasia congenita: a serious congenital abnormality with a relatively favorable prognosis]. / Amyoplasia congenita: een ernstige congenitale afwijking met relatief gunstige prognose.

After an uneventful pregnancy a girl was born with serious joint contractures and several fractures of the long bones. The family history was negative for congenital abnormalities. Based on the distinct clinical presentation the diagnosis was 'amyoplasia', which is a partial aplasia of skeletal muscles. The cause of amyoplasia is unknown. As well as the partial muscle aplasia, which is symmetrical and mainly affects the extremities, joint contractures and deep dimples in the skin around the joints are present. Several frequently associated abnormalities have been reported, including abdominal hernias, midface capillary haemangiomas and hypoplastic external genitalia. The condition is always sporadic; there is a striking discordance within monozygotic twins and the offspring of patients is normal. In contrast with the severe neonatal presentation, the clinical prognosis is relatively good owing to intensive multidisciplinary treatment and the normal intelligence of the patients.