BackgroundMultiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.MethodsThe phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient’s molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.ResultsThe most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.ConclusionsThis detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype–phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0244-7) contains supplementary material, which is available to authorized users.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.

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The case of a 10-year-old boy with Farber lipogranulomatosis with predominant joint involvement, subacute, laryngeal and tongue granulomas, microcytic anemia, elevated ESR and CRP, is presented. The boy had no signs of CNS and internal organ involvement. The disease manifested at 6 months; at 11 months the boy had widespread granulomatous polyarthritis with contractures, and juvenile idiopathic arthritis (JIA) was suggested. All antirheumatic therapies failed. Immunologic assessment revealed elevated serum interleukin-1β, increased T-helper, NK and CD25-positive cells, and circulating immune complexes. Our case with predominant rheumatologic manifestations illustrates a differential diagnosis of JIA.

Adult Refsum disease is an autosomal recessive peroxisomal disorder characterized by phytanic acid storage. Clinical symptoms usually begin in late childhood before the age of 20. Typical clinical presentation includes nyctalopia caused by retinitis pigmentosa, and anosmia. After 10-15 years, deafness, cerebellar ataxia, polyneuropathy, ichthyosis, and cardiac arrhythmia can occur.We report the case of a very late-onset adult Refsum disease presenting with marked cognitive decline and severe leukoencephalopathy, without peripheral nervous system involvement. Brain MRI showed a leukoencephalopathy involving the periventricular white matter, subcortical area, and the brainstem with relative sparing of juxtacortical U fibers. This was associated with severe cortical and subcortical atrophy with ventricle dilatation. MR spectroscopy showed a marked increase in the choline/NAA ratio. Elevated plasma phytanic acid level was found, whereas plasma levels of pristanic and very long chain fatty acids were normal. The patient is homozygous for a previously undescribed PHYH frameshift mutation. Whether the very unusual phenotype is related to this peculiar mutation remains unclear.This 72-year-old woman with a past history of left-eye congenital amaurosis, insulino-requerant diabetes, and elevated blood pressure came to medical attention because of progressive dementia and walking difficulties. She had no noticeable neurological problem until the age of 69, when she experienced balance difficulties and memory problems. A year later, after a fall, a C2 vertebra fracture was discovered. Within the next months, apragmatism (inability to wash or dress) was noticed along with a severe memory loss (she forgot the number and names of her children), nycthemeral rhythm inversion, and urinary incontinence. Neuropsychological tests showed severe frontal syndrome, dementia with spatiotemporal disorientation, and memory loss. Clinical examination disclosed gait apraxia reminiscent of frontal lobe dysfunction with no clear cerebellar ataxia. A brain magnetic resonance (MR) imaging showed a leukoencephalopathy involving the periventricular white matter, subcortical area, and the brainstem with relative sparing of juxtacortical U fibers (Fig. 1a, b). This was associated with severe cortical and subcortical atrophy with ventricle dilatation. MR spectroscopy showed a marked increase in the choline/NAA ratio (Fig. 1c).Electromyography showed no polyneuropathy but only bilateral carpal tunnel syndrome. Electroretinogram was normal in the right eye (not evaluable on the left). Cardiac