Novel KIF7 missense substitutions in two patients presenting with multiple malformations and features of acrocallosal syndrome.

We present two children who both had two missense mutations in the Kinesin Family Member 7 (KIF7) gene. A seven year old female with severe developmental delays, failure to thrive and growth retardation, infantile spasms, a cardiac vascular ring and right-sided aortic arch, imperforate anus, hydronephrosis with a right renal cyst, syndactyly and abnormal white matter was a compound heterozygote for c.3365C > G, predicting p.(Ser1122Trp) that was maternally inherited and c.2482G > A, predicting p.(Val828Met) that was paternally inherited. An eight year old female with severe developmental delays, epilepsy, left postaxial polydactyly of the hand and abnormalities of brain development including hydrocephalus, pachygyria and absence of the body and splenium of the corpus callous was a compound heterozygote for c.461G > A, predicting p.(Arg154Gln) and c.2959 G > A, predicting p.(Glu987Lys) that was maternally inherited and her father was unavailable for testing. The presentations in these children include features of acrocallosal syndrome, such as hypoplasia of the corpus callosum, enlarged ventricles, facial dysmorphism with a prominent forehead and broad halluces in the first child, but included atypical findings for individuals previously reported to have truncating mutations in KIF7, including imperforate anus, infantile spasms and severe growth retardation. We conclude that these phenotypes may result from the KIF7 sequence variants and abnormal hedgehog signaling, but that the full spectrum of KIF7-associated features remains to be determined.

Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions.

Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a well-recognized entity. However, the molecular underpinnings of this devastating disease are poorly understood. Here, we present genetic and neuropathological characterizations in two young women with fatal rapidly progressive ALS with basophilic inclusions. In one case, a germline mutation (P525L) was detected in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene, whereas no mutation was identified in the other case. Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum. In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei. In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein. These results underscore the importance of FUS mutations and pathology in rapidly progressive juvenile ALS. Furthermore, our study represents the first detailed characterizations of neuropathological findings in rapidly progressive juvenile ALS patients with a mutation in the FUS/TLS gene.

Therapeutics in duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3,500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child's quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

Infant botulism, type F, presenting at 54 hours of life.

We report a case of botulism in a 54-hour-old infant with rapidly progressive fulminant paralysis and rapid spontaneous recovery atypical for infant botulism. Clostridium baratii and type F botulinum neurotoxin were isolated from the patient's stool. This unique presentation with rapid recovery is consistent with pharmacokinetics of type F botulinum neurotoxin. Interestingly, a muscle biopsy also revealed pathologic changes early in the disease course. This article reports the youngest known case of infant botulism and only the third reported case of this disease caused by type F neurotoxin. Botulism should be considered in patients of any age with subacute or acute neuromuscular weakness.