Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1.

Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.

Mass spectrometry of apolipoprotein C-III, a simple analytical method for mucin-type O-glycosylation and its application to an autosomal recessive cutis laxa type-2 (ARCL2) patient.

Apolipoprotein C-III (apoCIII) is a small glycoprotein with a single mucin-type core-1 oligosaccharide and is analyzed by isoelectric focusing (IEF) for the diagnosis of genetic defects in O-glycan biosynthesis such as congenital disorders of glycosylation. In the present study, mass spectrometry of apoCIII, after a simple procedure for sample preparation using a small amount of serum, was demonstrated to be a reliable alternative to IEF. It allows reproducible glycan profiling and detection of unglycosylated species. This method was applied to an autosomal recessive cutis laxa type-2 patient and demonstrated decreased site occupancy by O-glycosylation.

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype.

BACKGROUND: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. METHODS: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1. RESULTS: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria. CONCLUSIONS: Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN.

Acquired cutis laxa associated with multiple myeloma.

Acquired cutis laxa, or generalized elastolysis, is a rare disease. One patient was found to have not only cutis laxa but also multiple myeloma.

Effects of disulfiram treatment in patients with Menkes disease and occipital horn syndrome.

The clinical and biochemical effects of disulfiram were evaluated in three boys with the disorders characterized by copper deficiency due to the defect of ATP7A. Two suffered from Menkes disease (MD) and one from occipital horn syndrome. Disulfiram was orally given, in addition to a parenteral administration of copper-histidine in the case of MD patients. Serum levels of copper and ceruloplasmin slightly increased in one MD patient, and he showed favorable emotional expression and behavior more often than before according to his caretakers. However, no obvious changes were observed in the other two patients. Serum ratios of noradrenaline to dopamine, and adrenaline to dopamine, which are thought to be the indicators of dopamine ß-hydroxylase activity, one of the copper requiring enzymes, were unaltered after disulfiram treatment. No adverse effects were recognized during the treatment period in all patients. Although the major improvement was not observed clinically or biochemically by disulfiram treatment so far, the trial will be continued to see the possible effects in these disorders with copper transport defect.

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type.

OBJECTIVE: To delineate a new syndrome of brain dysgenesis and cutis laxa based on the description of 11 patients belonging to nine unrelated families recruited through an international collaboration effort. METHODS: Careful clinical assessment of patients from birth to the age of 23 years with follow-up studies ranging from 3 to 20 years. Biochemical studies of serum proteins glycosylation by isoelectric focusing and capillary zone electrophoresis were performed in 10 patients. Brain MRI studies using conventional methods were analyzed in eight patients. RESULTS: An expanded clinical spectrum of a syndrome comprising facial dysmorphia (enlarged anterior fontanelles, downward slant of palpebral fissures, prominent root of the nose), a connective tissue disorder (inguinal hernia, hip dislocation, high myopia), and neurologic impairment was defined. Early developmental delay was followed by onset of generalized seizures by the end of the first decade and a subsequent neurodegenerative course. A defect of N- or N- plus O-glycosylation of serum transferrins and ApoCIII was observed in 10 patients. An unusual cobblestone-like cortical malformation over the frontal and parietal regions was seen in eight patients and cerebellar abnormalities, including two patients with Dandy-Walker malformation, were observed in three patients. CONCLUSIONS: Our results suggest that autosomal recessive cutis laxa, Debré type, initially considered a dermatologic syndrome, is a multisystemic disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome. It might represent a metabolic cause of Dandy-Walker malformation. It is associated with a deficient N- and-O glycosylation of proteins and shares many similarities with muscle-eye-brain syndromes.