Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Evaluating the efficacy of surgical excision and topical dimethyl sulphoxide (DMSO) in the treatment of equine cutaneous pythiosis.

BACKGROUND: Cutaneous pythiosis in horses is a chronic ulcerative granulomatous disease caused by the oomycete Pythium insidiosum. AIMS: The objective of the present study was to evaluate the response of cutaneous pythiosis in horses to surgical excision and topical dimethyl sulphoxide (DMSO). METHODS: Thirty horses were presented clinically with pruritus, fistulae discharging serosanguineous fluid, and output kunkers in different body areas (limb, abdomen, neck, and face). The clinical diagnosis was confirmed by isolation of the causative agent and histopathology. All animals were treated by surgical excision alone, or surgical excision followed by topical DMSO. The healing process was monitored every week macroscopically to evaluate the response to treatment until complete recovery. RESULTS: The existence of Pythium insidiosum was confirmed in all cases. Histologically, affected horses were characterized by granulation tissue with abundant eosinophils. The size of wounds and the clinical features of pythiosis lesions decreased more after surgical debridement with DMSO application than surgical excision alone. The cutaneous pythiosis lesions were completely recovered at 35 ± 7 and 60 ± 5 days after the surgical excision with topical DMSO and surgical excision alone, respectively. CONCLUSION: The combination of surgical excision and topical DMSO is found an effective treatment for cutaneous pythiosis in horses.

Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy.

Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet-like phenotype observed in Scn1b-/- mice. The 'negative' clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes.

Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.

Olfactory function and nasal nitric oxide.

OBJECTIVE: To determine the relationship between nasal nitric oxide (nNO) concentration and its influence on olfactory function. SETTING: Tertiary otolaryngology care centre. PARTICIPANTS: Sixty-four patients suffering from chronic rhinosinusitis and 20 healthy subjects participated. STUDY DESIGN: Prospective study. OUTCOME MEASURES: The nNO concentration was measured by chemiluminescence and olfactory thresholds were measured with the phenyl ethanol threshold of the Sniffin' Sticks. In chronic rhinosinusitis patients this measure was done preoperatively and 3 months after endoscopic sinus surgery. RESULTS: Healthy subjects had significantly higher nNO concentrations and better olfactory thresholds compared to the chronic rhinosinusitis patients, both before and after those had undergone sinus surgery. Olfactory thresholds and nNO concentrations remained unchanged after surgery in the chronic rhinosinusitis group. In the chronic rhinosinusitis group, nNO concentrations correlated positively with the olfactory threshold preoperatively (P < 0.0001) and 3 months after surgery (P < 0.05). In the control group, nNO production did not correlate with the olfactory thresholds (P > 0.05). CONCLUSION: Olfactory function and nNO concentration correlate in chronic rhinosinusitis patients but not in healthy subjects. This suggests that both parameters do rather not directly influence each other but it might be the inflammatory processes found in chronic rhinosinusitis that affects olfaction and nNO. Nasal nitric oxide produced by the paranasal sinuses seems not to directly influence olfactory function.