Fragile X syndrome [fra (X)] is currently accepted as the second most frequent chromosomal disorder associated with developmental disability. Although next to Down syndrome in frequency, no postmortem studies of confirmed adult cases had been reported. The autopsy examination of a 62-year-old, moderately retarded man with the fra (X) syndrome confirmed the preferential involvement of cerebral and testicular structures in this disorder. Dendritic spine abnormalities of the type observed in trisomic chromosomal disorders were associated with synaptic immaturity. Severe testicular hypogonadism accompanied bilateral macro-orchidism, normal penis, and unilateral hydrocele. Valvular, articular, and testicular interstitial compartments showed normal histochemical staining characteristics for glycoproteins and lipids.

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

K Kr ry ys st ty yn na a S Sz zy ym ma ań ńs sk ka a 1 1, ,2 2 , , A Ag gn ni ie es sz zk ka a Ł Łu ug go ow ws sk ka a , , M Mo on ni ik ka a B Be ek ki ie es si iń ńs sk ka a--F Fi ig ga at to ow ws sk ka a

Our material presents two patterns of white matter lesions in the brain of newborns dying with the clinical diagnosis of intrauterine or perinatal pathology: (1) classical periventricular ischemic infarction resulting in coagulative necrosis and (2) diffuse periventricular colliquative necrosis, in some cases involving the center of the cerebral convolutions. The majority of cases did not survive the first month of life. The cases with longer survival (up to six years) presented clinically with the syndrome of bilateral spastic cerebral palsy. Neuropathological examination showed dilation of the lateral ventricles, small cavities, and diffuse glial scars, not only in the periventricular white matter but also involving the axis of cerebral convolutions, as opposed to the relative sparing of cerebral cortex and other brain structures. These changes could be considered as evident or putative forms of a distinct type of perinatal brain damage.

Light microscopic, histochemical and electron-microscopic studies were made on the brain of a case (No. 1) with Sanfilippo disease, type A. In this case pigment preparations of the isocortex have been demonstrated. Ultrastructural investigations of the skin biopsies (his two male siblings) were also studied (cases 2, 3). Our three siblings of MPS III A, have demonstrated ceroid lipofuscin storage in the brain (case No. 1) and skin biopsies (cases No. 2 and 3) in addition to histological features of MPS. The biochemical studies (enzymatic identification) were made in the cultures of fibroblasts. Also, urine quantitative studies for MPS and N-sulfonate to hexosamino ratio were performed.

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