Duchenne muscular dystrophy in a girl with chromosomal translocation

It is reported the case of an 8-year-old girl with clinical and laboratory findings suggestive of Duchenne muscular dystrophy who had a chromosome translocation involving the X chromosome, 46,X,t(Bp+,Xq-). A review about Duchenne muscular dystrophy in females is made, with emphasis about chromosome abnormalities, mainly chromosome translocations.     

Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication.

OBJECTIVE: To assess alterations in brain metabolites of patients with Pelizaeus-Merzbacher disease (PMD) with the proteolipid protein gene 1 (PLP1) duplications using quantitative proton MRS. METHODS: Five unrelated male Japanese patients with PMD with PLP1 duplications were analyzed using automated proton brain examination with the point resolved spectroscopy technique (repetition and echo time of 5,000 and 30 msec). Localized spectra in the posterior portion of the centrum semiovale were acquired, and absolute metabolite concentrations were calculated using the LCModel. RESULTS: Absolute concentrations of N-acetylaspartate (NAA), creatine (Cr), and myoinositol (MI) were increased by 16% (p < 0.01), 43% (p < 0.001), and 31% (p < 0.01) in patients with PMD as compared with age-matched controls. There was no statistical difference in choline concentration. CONCLUSION: The increased concentration of NAA, which could not be detected by previous relative quantitation methods, suggests two possibilities: axonal involvement secondary to dysmyelination, or increased cell population of oligodendrocyte progenitors. Elevated Cr and MI concentrations may reflect the reactive astrocytic gliosis. Our study thus emphasizes the importance of absolute quantitation of metabolites to investigate the disease mechanism of the dysmyelinating disorders of the CNS.     

PLP1 gene duplication as a cause of the classic form of Pelizaeus-Merzbacher disease - case report

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelination disorder of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene located at Xq22 and encoding the major myelin component in CNS, proteolipid protein 1 (PLP1). The disease is clinically heterogeneous. Phenotypes are generally categorized into classic and connatal forms. Connatal PMD has more rapid progression with early death, while patients with classic PMD generally survive to adulthood. Both forms of the disease are caused by point mutations as well as rearrangements - multiplication (mainly duplication) and deletion of the PLP1 gene. We present a case of a male patient affected by the classic form of PMD with benign course, except severe dysarthria with the characteristic laryngeal stridor, which is more typical for connatal form of the disease. The diagnosis has been confirmed at the molecular level. The patient has duplication of all 7 exons of the PLP1 gene. This duplication was inherited from the patient's mother, who is an unaffected carrier of the mutation. The patient's family pedigree analysis revealed the interfamilial variability of the phenotype among affected male relatives.     

LGI‐1 antibody encephalitis in a seven‐year‐old girl

LGI‐1 antibody encephalitis is a rare autoimmune limbic encephalitis which has been reported predominantly in adults. Seizures in LGI‐1 antibody encephalitis exhibit significant semiological variability. Faciobrachial dystonic seizures are characteristically seen in this condition and have so far been described only in adults. Other seizure types have also been reported. We describe the case of a seven‐year‐old girl with LGI‐1 limbic encephalitis who presented with acute new‐onset seizures, and rapidly deteriorated over the course of a few weeks with very frequent seizures and encephalopathy, becoming non‐verbal and non‐ambulatory. The electroclinical presentation of this child with LGI‐1 encephalitis makes this case unique and further highlights the importance of a high index of suspicion for diagnosis in young children. Early diagnosis can lead to prompt and appropriate treatment with immunotherapy, and potential harmful treatments such as pharmacological coma can be avoided. To the best of our knowledge, this is the youngest case ever reporter. [Published with video sequences]     

PLP/DM20 Expression and turnover in a transgenic mouse model of pelizaeus‐merzbacher disease

The most common cause of Pelizaeus‐Merzbacher (PMD) is due to duplication of the PLP1 gene but it is unclear how increased gene dosage affects PLP turnover and causes dysmyelination. We have studied the dynamics of PLP/DM20 in a transgenic mouse model of PMD with increased gene dosage of the proteolipid protein gene (Plp1). The turnover of PLP/DM20 were investigated using an ex‐vivo brain slice system and cultured oligodendrocytes. Homozygous mice have reduced PLP translation, markedly enhanced PLP degradation, and markedly reduced incorporation of PLP into myelin. Proteasome inhibition (MG132) prevented the enhanced degradation. Numerous autophagic vesicles are present in homozygous transgenic mice that may influence protein dynamics. Surprisingly, promoting autophagy with rapamycin decreases the degradation of nascent PLP suggesting autophagic vacuoles serve as a cellular storage compartment. We suggest that there are multiple subcellular fates of PLP/DM20 when overexpressed: the vast majority being degraded by the proteasome, a proportion sequestered into autophagic vacuoles, probably fused with endolysosomes, and only a small proportion entering the myelin sheath, where its association with lipid rafts is perturbed. Transgenic oligodendrocytes have fewer membrane sheets and this phenotype is improved with siRNA‐mediated knockdown of PLP expression that promotes the formation of MBP+ myelin‐like sheets. This finding suggests that RNAi technology is in principle applicable to improve CNS myelination when compromised by PLP/DM20 overexpression. © 2010 Wiley‐Liss, Inc.     

A 13‐year‐old girl with proximal weakness and hypertrophic cardiomyopathy with danon disease

Danon disease is caused by deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2). It is characterized clinically by cardiomyopathy, myopathy, and mental retardation in boys. Herein we report a 13‐year‐old female patient with Danon disease who presented with early‐onset skeletal myopathy and cardiomyopathy. She had a de novo novel mutation in the LAMP2 gene, and her muscles showed many autophagic vacuoles with sarcolemmal features and complete absence of LAMP‐2 expression. To the best of our knowledge, this girl is one of the earliest‐onset manifesting carriers of Danon disease with typical muscle pathology. Muscle Nerve, 2010     

Bilateral periventricular nodular heterotopia and lissencephaly in an infant with unbalanced t(12;17)(q24.31; p13.3) translocation

Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene (LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3-->pter and partial trisomy of 12q24.3-->qter. No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3.     

Intra‐ and inter‐network functional alterations in Parkinson's disease with mild cognitive impairment

Mild cognitive impairment (MCI) is prevalent in 15%–40% of Parkinson's disease (PD) patients at diagnosis. In this investigation, we study brain intra‐ and inter‐network alterations in resting state functional magnetic resonance imaging (rs‐fMRI) in recently diagnosed PD patients and characterise them as either cognitive normal (PD‐NC) or with MCI (PD‐MCI). Patients were divided into two groups, PD‐NC (N = 62) and PD‐MCI (N = 37) and for comparison, healthy controls (HC, N = 30) were also included. Intra‐ and inter‐network connectivity were investigated from participants’ rs‐fMRIs in 26 resting state networks (RSNs). Intra‐network differences were found between both patient groups and HCs for networks associated with motor control (motor cortex), spatial attention and visual perception. When comparing both PD‐NC and PD‐MCI, intra‐network alterations were found in RSNs related to attention, executive function and motor control (cerebellum). The inter‐network analysis revealed a hyper‐synchronisation between the basal ganglia network and the motor cortex in PD‐NC compared with HCs. When both patient groups were compared, intra‐network alterations in RSNs related to attention, motor control, visual perception and executive function were found. We also detected disease‐driven negative synchronisations and synchronisation shifts from positive to negative and vice versa in both patient groups compared with HCs. The hyper‐synchronisation between basal ganglia and motor cortical RSNs in PD and its synchronisation shift from negative to positive compared with HCs, suggest a compensatory response to basal dysfunction and altered basal‐cortical motor control in the resting state brain of PD patients. Hum Brain Mapp 38:1702–1715, 2017 . © 2016 Wiley Periodicals, Inc.     

Twenty-year behavioral follow-up of a 1;13 chromosomal translocation and Mobius syndrome presenting with poor impulse control, exhibitionism, and aggression

Mobius syndrome is a rare disorder characterized by agenesis or aplasia of the facial or abducens nerve motor nuclei and other features including central nervous system and behavioral abnormalities. We report an adult case of Mobius syndrome variant presenting with poor impulse control, aggression, and exhibitionism. Karyotyping revealed a 46 XY, t(1;13)(p34.3;q12.3) translocation. The subject had been presented 20 years previously as the index case of a three-generation pedigree.