Development of a patient-reported outcome measure for upper limb function in Duchenne muscular dystrophy: DMD Upper Limb PROM.

AIM: To develop a patient-reported outcome measure (PROM) assessing upper limb function related to activities of daily living (ADL) that cannot be observed in a clinical setting, specifically for patients with Duchenne muscular dystrophy (DMD) across a wide age range, applicable in the different stages of the disease. METHOD: The developmental process was based on US Food and Drug Administration guidelines. This included item generation from a systematic review of existing tools and expert opinion on task difficulty and relevance, involving individuals with DMD. Cultural aspects affecting ADL were taken into consideration to make this tool applicable to the broad DMD community. Items were selected in relation to a conceptual framework reflecting disease progression covering the full range of upper limb function across different ADL domains. RESULTS: After pilot testing and iterative Rasch analyses, redundant or clinically irrelevant items were removed. The final questionnaire consists of 32 items covering four domains of ADL (food, self-care, household and environment, leisure and communication). Test-retest reliability was excellent. INTERPRETATION: A DMD-specific upper limb PROM was developed on the basis of clinical relevance and psychometric robustness. Its main purpose is to document the patient self-reported natural history of DMD and assess the efficacy of interventions.

Relationships between motor impairments and activity limitations in patients with neuromuscular disorders.

AIM: The strength and nature of the relationships between motor impairments and activity limitations assessed by the ACTIVLIM questionnaire were investigated in 245 patients with neuromuscular disorders. METHODS: Measures of motor impairments consisted of: (1) a grip strength test using a Jamar dynamometer, (2) a Manual Muscle Testing bilaterally performed in 18 muscle groups and (3) a gait speed spontaneously adopted by the patients using the 10 m timed walking test. RESULTS: Activity limitations were poorly correlated with grip strength in both hands (r = 0.3 and 0.36) and moderately correlated with gait speed (r = 0.53). Spearman's coefficients of correlation between the manual muscle testing and activity limitations were moderate to very poor (rho = 0.5 to 0.17). CONCLUSION: The relationships between motor impairments and activity limitations are not straightforward in patients with neuromuscular disorders, indicating that the activity limitations should be separately assessed and cannot be simply inferred from motor impairment measures.

RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis of glycans and in the attachment of glycans to lipids and proteins. Actually, some 42 CDG are known including defects in protein N-glycosylation, in protein O-glycosylation, in lipid glycosylation, and in multiple and other glycosylation pathways. Most CDG are multisystem diseases and a large number of signs and symptoms have already been reported in CDG. An exception to this is deafness. This symptom has not been observed as a consistent feature in CDG. In 2008, a novel defect was identified in protein N-glycosylation, namely in RFT1. This is a defect in the assembly of N-glycans. RFT1 is involved in the transfer of Man(5)GlcNAc(2)-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. According to the novel nomenclature (non-italicized gene symbol followed by -CDG) this defect is named RFT1-CDG. Recently, three other patients with RFT1-CDG have been reported and here we report two novel patients. Remarkably, all six patients with RFT1-CDG show sensorineural deafness as part of a severe neurological syndrome. We conclude that RFT1-CDG is the first 'deafness-CDG'. CDG should be included in the work-up of congenital, particularly syndromic, hearing loss.

Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne.

Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.

Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients.

The aim of this prospective longitudinal multi centric study was to evaluate the correlation between the Hammersmith Functional Motor Scale and the 20 item version of the Motor Function Measure in non ambulant SMA children and adults at baseline and over a 12 month period. Seventy-four non-ambulant patients performed both measures at baseline and 49 also had an assessment 12 month later. At baseline the scores ranged between 0 and 40 on the Hammersmith Motor function Scale and between 3 and 45 on the Motor Function Measure 20. The correlation between the two scales was 0.733. The 12 month changes ranged between -11 and 4 for the Hammersmith and between -11 and 7 for the Motor Function Measure 20. The correlation between changes was 0.48. Our results suggest that both scales provide useful information although they appeared to work differently at the two extremes of the spectrum of abilities. The Hammersmith Motor Function Scale appeared to be more suitable in strong non ambulant patients, while the Motor Function Measures appeared to be more sensitive to capture activities and possible changes in the very weak patients, including more items capturing axial and upper limb activities. The choice of these measures in clinical trials should therefore depend on inclusion criteria and magnitude of expected changes.

Six minute walk test in type III spinal muscular atrophy: a 12month longitudinal study.

The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was -1.46 (SD 50.1; range: -183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients.

Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2 gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype-phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs.

Fibrodysplasia ossificans progressiva: still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who "turned to wood", its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable "clues from the fly" reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.

Symptomatic unilateral dolicho-ectasia of the intracranial arteries in a child.

Dolicho-ectasia of the left posterior cerebral artery and internal carotid artery in a 5-year-old boy is reported. There was compression of the brainstem, the mammillary bodies and the optic tract. The value of MR angiography in the diagnosis of this vascular anomaly is demonstrated. Dolicho-ectasia of more than one cerebral artery in a child is extremely rare.

Unilateral thalamic haemorrhage in the pre-term and full-term newborn.

One full-term and three premature newborns with a unilateral thalamic haemorrhage are reported. The lesion was diagnosed using cranial ultrasonography and confirmed in three using magnetic resonance imaging. Severe perinatal asphyxia occurred in all infants. The neonatal clinical history, subsequent neuro-developmental outcome and neuroimaging findings are discussed. As the prognosis appears to be much better than for infants with bilateral thalamic densities, it is important that this type of lesion is recognised as a separate entity.

Association of hyperprolinaemia type I and heparin cofactor II deficiency with CATCH 22 syndrome: evidence for a contiguous gene syndrome locating the proline oxidase gene.

Increased proline levels were found in plasma of a girl with slight psychomotor retardation, epilepsy, obesity, scoliosis, hypocalcaemia, variable lymphocytopenia and facial dysmorphy suggestive of CATCH 22 syndrome. Fluorescence in situ hybridization indicated the presence of a submicroscopic 22q11 deletion, confirming this diagnosis. Further investigation showed evidence that the patient was heterozygous for heparin cofactor II deficiency and for hyperprolinaemia type I, a proline catabolic disorder due to proline oxidase deficiency. This association extends the CATCH 22 syndrome and suggests that expression of the proline oxidase gene depends on the chromosome 22q11 region.

Fetal akinesia sequence caused by nemaline myopathy.

Nine patients with the characteristic signs of fetal akinesia sequence (polyhydramnion, multiple joint contractures and lung hypoplasia) are described. In 8 of the 9 patients nemaline myopathy could be demonstrated with histology. The ninth patient presented the same phenotype as his 4 affected siblings in whom the nemaline myopathy could be histologically proven. Seven of the patients belonged to 2 families; the other 2 patients were isolated cases. In one fetal case nemaline myopathy was documented at week 22 of gestation. These observations demonstrate that nemaline myopathy can cause the fetal akinesia sequence, with onset of first symptoms as early as the beginning of the second trimester of pregnancy.

Unusual molecular findings in autosomal recessive spinal muscular atrophy.

All three types of autosomal recessive spinal muscular atrophy map to chromosome 5q11.2-q13.3 and are associated with deletions or mutations of the SMN (survival motor neurone) gene. The availability of a test to distinguish between the SMN gene and its nearly identical centromeric copy cBCD541 allows molecular diagnosis. We have analysed patients from 24 Belgian and 34 Turkish families for the presence or absence of a deletion in the SMN gene. A homozygous deletion in the SMN gene was seen in 90% of unrelated SMA patients. A non-radioactive SSCP assay allows for a semiquantitative analysis of the copy number of the centromeric and SMN genes. Hence, direct carrier detection has become feasible under certain conditions. We observed a phenotypically normal male, father of an SMA type I patient, presenting with only a single copy of the SMN gene and lacking both copies of the cBCD541 gene. This illustrates that a reduction of the total number of SMN and cBCD541 genes to a single SMN copy is compatible with normal life. In another SMA type I family, there is evidence for a de novo deletion of the centromeric gene in a normal sib. This observation illustrates the susceptibility of the SMA locus to de novo deletions and rearrangements.

Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring.

The authors report 1-year prospective data on eight patients with Friedreich ataxia. Idebenone did not halt the progression of ataxia. At the end of therapy, cardiac ultrasound demonstrated significant reduction of cardiac hypertrophy in six of eight patients. Cardiac strain and strain rate imaging showed that the reduction of hypertrophy is preceded by an early and linear improvement in cardiac function. Idebenone reduced erythrocyte protoporphyrin IX levels in five of six patients with elevated baseline levels; however, changes did not consistently relate to cardiac improvement.