Mireia del Toro

Brainstem dysgenesis: report of five patients with congenital hypotonia, multiple cranial nerve involvement, and ocular motor apraxia

This paper reports three females and two males with a distinctive congenital syndrome characterized by severe congenital hypotonia, facial diplegia, jaw ankylosis, velo‐pharyngeal incoordination, pyramidal tract signs, and ocular motor apraxia. Patients were followed up at ages ranging from 20 months to 16 years. All cases of this syndrome are sporadic, without dysmorphological features, chromosomal, or MRI brain abnormalities. Electrophysiological studies indicate the brainstem as the site of the neurological dysfunction. Postmortem CNS study of one of the patients demonstrated neuronal depletion of the IV, VII, VIII, and IX cranial nerve nuclei and intact morphology of the cerebral hemispheres. A vascular accident, early in foetal life, is the most likely cause of the clinical picture. The extent of brainstem involvement and its related clinical findings distinguishes these patients from those with Moebius, Pierre Robin, or Cogan syndromes. Outcome is better than what could be anticipated during the first few months of life given the severity of symptoms. Intelligence or developmental quotients are within the normal range for their age. Facial hypomimia, feeding, and speech articulatory performance difficulties are the main disabilities observed in these patients at follow‐up.

Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease

Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1 were recently identified in patients with fatal encephalopathy displaying a biochemical phenotype consistent with defects in lipoic acid-dependent enzymatic activities and respiratory chain complexes. This discovery highlighted the molecular function of NFU1 as an iron-sulfur(Fe-S) cluster protein necessary for lipoic acid biosynthesis and respiratory chain complexes activities. To understand the pathophysiological mechanisms underlying this disease we have characterized the protein expression profiles of patients carrying NFU1 mutations. Fibroblasts from patients with the p.Gly208Cys mutation showed complete absence of protein-bound lipoic acid and decreased SDHA and SDHB subunits of complex II. In contrast, subunits of other respiratory chain complexes were normal. Protein lipoylation was also decreased in muscle and liver but not in other tissues available (brain, kidney, lung) from NFU1 patients. Although levels of the respiratory chain subunits were unaltered in tissues, BN-PAGE showed an assembly defect for complex II in muscle, consistent with the low enzymatic activity of this complex. This study provides new insights into the molecular bases of NFU1 disease as well as into the regulation of NFU1 protein in human tissues. We demonstrate a ubiquitous expression of NFU1 protein and further suggest that defects in lipoic acid biosynthesis and complex II are the main molecular signature of this disease, particularly in patients carrying the p.Gly208Cys mutation.

Progressive vacuolating glycine leukoencephalopathy with pulmonary hypertension.

To report two unrelated patients with a new phenotype of nonketotic hyperglycinemia associated with idiopathic pulmonary hypertension. Clinical findings included rapidly progressive neurological deterioration with onset in the first year of life characterized by developmental regression without seizures or electroencephalogram abnormalities during follow‐up. Both patients died before the age of 18 months. Glycine cleavage system deficiency was confirmed by enzymatic studies in frozen liver. Molecular analysis in the related genes showed no pathogenic mutation. Radiological and pathological findings were consistent with progressive vacuolating encephalopathy. Our patients with biochemical and enzymatic parameters consistent with atypical nonketotic hyperglycinemia. The clinical and radiological evolution, as progressive vacuolating leukoencephalopathy and the association with pulmonary hypertension constitute a previously unrecognized variant. Ann Neurol 2006;60:148–152

Painful ophthalmoplegia with reversible carotid stenosis in a child

Painful ophthalmoplegia in childhood has different causes. One is Tolosa-Hunt syndrome, in which a first episode may be difficult to diagnose because of its clinical similarity to ophthalmoplegic migraine. A 10-year-old male with painful ophthalmoplegia and a cavernous sinus inflammation associated with an intracavernous carotid stenosis demonstrated by magnetic resonance imaging and angiography is reported. These findings resolved in follow-up imaging. This report suggests that in the presence of painful ophthalmoplegia, magnetic resonance imaging detection of cavernous sinus inflammation can facilitate the diagnosis of Tolosa-Hunt syndrome when other causes are excluded.

A leaky splicing mutation in NFU1 is associated with a particular biochemical phenotype. Consequences for the diagnosis

Mutations in NFU1 were recently identified in patients with fatal encephalopathy. NFU1 is an iron-sulfur cluster protein necessary for the activity of the mitochondrial respiratory chain complexes I-II and the synthesis of lipoic acid. We report two NFU1 compound heterozygous individuals with normal complex I and lipoic acid-dependent enzymatic activities and low, but detectable, levels of lipoylated proteins. We demonstrated a leaky splicing regulation due to a splice site mutation (c.545+5G>A) that produces small amounts of wild type NFU1 mRNA that might result in enough protein to partially lipoylate and restore the activity of lipoic acid-dependent enzymes and the assembly and activity of complex I. These results allowed us to gain insights into the molecular basis underlying this disease and should be considered for the diagnosis of NFU1 patients.

Contribution of syntaxin 1A to the genetic susceptibility to migraine: a case-control association study in the Spanish population.

Migraine is a common neurological disorder with a complex inheritance pattern. Mutations in genes encoding proteins that are involved in ion transport across the neuronal membrane have been linked to rare monogenic variants of migraine. These or other related genes and proteins are also candidates to be involved in the inherited predisposition to the more common forms of migraine without aura (MO) or migraine with aura (MA). One of these proteins, syntaxin 1A, encoded by the STX1A gene, is a key molecule in ion channel regulation and synaptic exocytosis. We assessed the contribution of STX1A to migraine by analyzing three SNPs that cover the entire gene (rs6951030-rs941298-rs4363087), in a case-control association study in 210 migraine patients (102 MO, 86 MA, 22 hemiplegic migraine) and 210 sex-matched unrelated controls. The single-marker analysis revealed significant differences in both allele frequencies (P=0.0087, OR=1.48) and genotype distributions (P=0.0133) of the rs941298 SNP between migraineurs and controls, with an overrepresentation of T-allele carriers in the migraine sample (OR=1.78). We subsequently performed a haplotype-based analysis and observed evidence of an overrepresentation of the A-T-G (rs6951030-rs941298-rs4363087) allelic combination in migraine patients and an increased frequency of carriers of this risk haplotype (P=0.008, OR=1.71). These differences remained significant when patients were subdivided into MO and MA. When the control series was enlarged for rs941298, we confirmed the association only with the whole migraine group.

Proteomic analysis in cerebrospinal fluid of patients with atypical nonketotic hyperglycinemia and pulmonary hypertension - A pilot study.

A variant phenotype of nonketotic hyperglycinemia has been described by our group associated with pulmonary hypertension. The aim of this study is to investigate the cerebrospinal fluid proteomes to get an insight into this neurodegenerative process producing leukoencephalopathy with white matter spongiform degeneration. DIGE and MALDI‐TOF‐TOF analyses were performed to carry out the proteomic study of four patients against three normal controls and one additional control of a classical nonketotic hyperglycinemia. The differential proteomic analysis showed a displacement of some series of spots toward the acidic side. The shifted proteins showed a high degree of carbonylation and increased methionine sulfoxidation was found in cystatin C and in vitamin‐D‐binding protein. These findings in addition to the increase of serum malondialdehyde concentration provide evidence of an oxidative stress in the patients under study, which is probably systemic rather than mainly confined to the CNS. The similarities of our findings with those found in other neurodegenerative diseases suggest that oxidative damage is commonly involved in these pathologies. DIGE technology improves the 2‐D PAGE differential analysis and it is suitable in proteomic studies with a small number of cases.

Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program

There is a growing interest in evaluating the effectiveness of enzyme replacement therapy (ERT) with elosulfase alfa in patients with mucopolysaccharidosis type IVA (MPS-IVA) under real-world conditions. We present the experience of seven pediatric MPS-IVA patients from the Spanish Morquio-A Early Access Program. Efficacy was evaluated based on the distance walked in the 6-min walking test (6-MWT) and the 3-min-stair-climb-test (3-MSCT) at baseline and after 8 months of ERT treatment. Additionally, urinary glycosaminoglycans were measured, and a molecular analysis of a GALNS mutation was performed. The health-related quality of life was evaluated using the EuroQoL (EQ)-5D-5 L. The distance walked according to the 6-MWT ranged from 0 to 325 m at baseline and increased to 12–300 m after 8 months with elosulfase alfa (the walked distance improved in all patients except one). An increase was observed for the two patients who had to use a wheelchair. Improvements were also observed for the 3-MSCT in four patients, whereas two patients showed no changes. Three patients showed an improvement in the EQ-VAS score, whereas the scores of three patients remained stable. Regarding urinary glycosaminoglycans measurements, an irregular response was observed. Our results showed overall improvement in endurance and functionality after 8 months of elosulfase alfa treatment in a heterogeneous subset of MPS IVA patients with severe clinical manifestations managed in a real-world setting.

Cobalamin disorder CblC presenting with hemolytic uremic syndrome and pulmonary hypertension

ombined homocystinuria and methylmalonic aciduria cbl-C ype is an inborn error of metabolism of vitamin B12 that leads o increased levels of homocysteine and methylmalonic acid. he spectrum of clinical manifestations and disease severity is road. Atypical hemolytic uremic syndrome (aHUS) and pulonary hypertension can be the first manifestations of the isease. We present a rare case of cbl-C, with aHUS, recurrent pulonary edema and severe pulmonary hypertension (PAH): A -year-old boy was admitted to the Pediatric Intensive Care nit (PICU) with severe hypertension and pulmonary edema, oth attributed to renal failure due to aHUS. He had a hisory of chronic hemolytic anemia of unknown origin since the ge of 15 months and aHUS of unknown etiology had been iagnosed a month earlier. Treatment with eculizumab (anti5 monoclonal antibody) had been administered, as primary HUS had been suspected. Parents were a healthy couple from orth Africa with a low level of consanguinity and had two ther healthy children. During PICU admission, our patient resented with arterial hypertension requiring multiple drugs, ecurrent episodes of pulmonary edema and progressive renal ailure ensued requiring continuous veno-venous hemofiltraion on day 7. Serial echocardiographic studies demonstrated rogressive pulmonary hypertension causing acute cor pulonale. Pulmonary thromboembolism was ruled out by a horacic CT scan. The diagnostic workup (Table 1) included kidney biopsy that showed a thrombotic microangiopahy (TMA) (Fig. 1). A panel for autoimmune diseases was egative. The diagnostic workup for metabolic inborn errors f metabolism was compatible with homocystinuria and ethylmalonic aciduria type cbl-C. Treatment with hydroxy-