Marinesco–Sjögren syndrome (MSS) isan autosomal recessive multiorgandisorder showing clinical andgenetic heterogeneity. The keyfeatures of MSS include cerebellarataxia, early bilateral cataracts,delayed motor development, andvarying degrees of mental retardation.Patients with a subtype ofMSS with myoglobinuria and neuropathyhave been linked to chromosome18qter, and recently alocus for classical MSS has beenlocalized on chromosome 5q31.

PURPOSE To assess the clinical picture and molecular genetics of 14 Finnish families with dominant optic atrophy (DOA). METHODS The clinical status of family members was based on the assessment of visual acuity, colour vision, visual fields and optic nerve appearance; 31 individuals were affected, two suspect and 21 unaffected. A total of 30 coding exons and exon- intron boundaries of the OPA1 gene were sequenced in order to detect mutations. RESULTS Half the patients were diagnosed at the age of < or = 20 years. Ten out of 20 affected individuals followed up for > or = 6 years had a progressive disease and 10 had a stable disease. According to WHO criteria, 36% of the affected patients were visually handicapped. Eight OPA1 pathogenic mutations, all but one novel, and 18 neutral polymorphisms were detected. CONCLUSION The most sensitive indicators of DOA were optic disc pallor and dyschromatopsia. With molecular genetic analysis, asymptomatic mutation carriers and DOA cases with a mild clinical outcome were ascertained. No mutational hotspot or Finnish major mutation in the OPA1 gene could be demonstrated as most families carried a unique mutation. No obvious genotype- phenotype correlation could be detected. Detailed clinical assessment and exclusion of non-DOA families prior to mutation screening are necessary for obtaining a high mutation detection rate.

We report on a 23-month-old boy with bilateral cleft lip and palate, marked hypertelorism, frontal bossing and severe bilateral, asymmetric hypoplasia of toes. The mother used bisoprolol, naproxen and sumatriptan for migraine until the fifth postmenstrual week of pregnancy. We suggest that this patient's features represent a previously undescribed entity of as yet unknown aetiology.

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Aβ42/43 but weakly or not at all for Aβ40 isoforms of the amyloid β peptide (Aβ). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related pHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum

We present 18 children with velocardiofacial syndrome. A palatal or a submucous cleft was observed in 10 patients, while 8 had no cleft. Seven patients had minor anomalies in the CT scan, but their significance is unclear. These anomalies as well as structural cardiac malformations occurred more often in the non-cleft patients. Cleft palate and velopharyngeal insufficiency were not the only causes of speech problems in these children. In the velocardiofacial syndrome speech disorder should be recognized and carefully analyzed with phoniatric and neuropsychological methods.

Uniform neuropathological changes are described in eight cases of the progressive encephalopathy syndrome with edema, hypsarrhythmia and optic atrophy (PEHO syndrome). Two of the autopsied patients were sisters and two other cases were familial. Macroscopically, cerebral and pronounced cerebellar atrophy was seen, the essential histopathological lesions being confined to the cerebellar cortex and the optic nerve. There was a severe neuronal loss in the inner granular layer of the cerebellum. The Purkinje cells were relatively preserved in number although reduced in size, deformed and slightly disaligned. Their dendrites were horizontally oriented and the proximal axons contained abundant torpedoes. The molecular layer was narrow. The optic nerves were atrophic. Serial neuroimaging studies showed that the disease process is operative during the postnatal period, although a prenatal onset cannot be excluded. An aberrant expression of immunoreactivity against the 200-kDa neurofilament polypeptide in Purkinje cell perikarya indicated disorganization of the cytoskeleton of these cells. The combination of clinical and pathological features of our patients differs from that observed in the few published cases of so-called primary degeneration of the granular layer. Infantile cerebello-optic atrophy, clinically characterized by seizures, blindness and early arrest in psychomotor development, thus seems to constitute a new autosomal recessive disorder.

Uniform neuropathological changes are described in eight cases of the progressive encephalopathy syndrome with edema, hypsarrhythmia and optic atrophy (PEHO syndrome). Two of the autopsied patients were sisters and two other cases were familial. Macroscopically, cerebral and pronounced cerebellar atrophy was seen, the essential histopathological lesions being confined to the cerebellar cortex and the optic nerve. There was a severe neuronal loss in the inner granular layer of the cerebellum. The Purkinje cells were relatively preserved in number although reduced in size, deformed and slightly disaligned. Their dendrites were hirozontally oriented and the proximal axons contained abundant torpedoes. The molecular layer was narrow. The optic nerves were atrophic. Serial neuroimaging studies showed that the disease process is operative during the postnatal period, although a prenatal onset cannot be excluded. An aberrant expression of immunoreactivity against the 200-kDa neurofilament polypeptide in Purkinje cell perikarya indicated disorganization of the cytoskeleton of these cells. The combination of clinical and pathological features of our patients differs from that observed in the few published cases of so-called primary degeneration of the granular layer. Infantile cerebello-optic atrophy, clinically characterized by seizures, blindness and early arrest in psychomotor development, thus seems to constitute a new autosomal recessive disorder.

The PEHO syndrome (progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy) is an early onset neurodegenerative disorder presenting with infantile spasms, profound psychomotor retardation, hypotonia, and loss of visual contact. The patients have characteristic facial features and a typical deviation of gaze upwards or sidewards. In 16 out of 18 patients, considered to have the PEHO syndrome on the basis of neuropathological or neuro-radiological studies, atrophic optic discs with absent pupillary reactions to light and extinguished visual evoked potentials were noted after two years of age. Two patients whose radiographic findings suggested the PEHO syndrome did not develop optic atrophy; in these cases the diagnosis of the true PEHO syndrome remains questionable. A histological study of the eyes of three patients showed extremely attenuated nerve fibre and ganglion cell layers with loss of nerve fibres and myelin sheaths from the optic nerves.Sixteen other patients with a clinical suspicion of the PEHO syndrome but with different neuropathological or neuroradiological findings frequently showed pale optic discs suggesting the possibility of optic atrophy, but visual evoked potentials could be elicited in most of them. In two of these cases a histopathological examination of the eye was undertaken; in both cases the retina and the optic nerve were normal.

Summary: Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome) is an apparently autosomal recessive disorder manifested by infantile spasms, severe hypotonia, and early arrest of psychomotor development. Subcutaneous edema in the limbs, typical facial features, and blindness with optic atrophy are also present. Neuropathologic and radiographic studies show progressive brain atrophy, which is accentuated infratentorially. We recorded 85 EEGs from 10 patients between the ages of 3 weeks and 12.7 years; follow‐up ranged from 7 months to 12.1 years. The infantile spasms were preceded by other neurological symp‐ toms in all patients. Seven of nine patients showed focal or generalized epileptiform activity or abnormal EEG background. All patients developed hypsarrhythmia, first recorded between 3 and 11 months of age, that was resistant to therapy with ACTH and antiepileptic drugs. After the hypsarrhythmia disappeared, five patients showed slow spike‐wave activity generally seen in the Lennox‐Gastaut syndrome, and three patients showed background EEG abnormality with generalized or diffuse paroxysmal activity. There were no specific EEG features that could help in the diagnosis of PEHO. The PEHO syndrome should be borne in mind in the diagnostic work‐up of patients with infantile spasms, so that potentially harmful treatment can be avoided, and the parents can be counseled about the inheritability of the disorder.