Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume

Abstract

Juvenile Huntington disease (JHD) is a rare clinical entity characterized by disease onset before the age of 21. JHD accounts for <10% of Huntington disease patients. Transmission of JHD is paternal in 80-90% of cases. Patients with JHD usually carry more than 60 CAG repeats within the HTT gene. We report here on a 23-month-old boy presenting with global developmental delay first noted at 18 months of age. Clinical examination showed truncal hypotonia, postural and intentional tremor, limb rigidity, and ataxia. Cerebral magnetic resonance imagery (MRI) showed reduced cerebellar volume. Six months later, his 47-year-old father was seen for a 4-year history of progressive dementia with severe behavioral disturbance and chorea. Cerebral MRI showed discrete global and caudate atrophy. DNA analysis revealed a very large and heterogeneous expansion (210-250 CAG) in the child and a 43 CAG expansion of the HTT gene in the father. This unusual case demonstrates that very early onset JHD due to large CAG expansions should be considered in cases of global developmental delay associated with reduced cerebellar volume, including cases without known HD family history.

Pathogenic Cellular Phenotypes are Germline Transmissible in a Transgenic Primate Model of Huntington's Disease

“…rHD-ESCs express mutant HTT and form intranuclear inclusion, a classical cellular feature of HD. Notably, mosaicism of the pathogenic polyQ region in the sperm as well as derived ESCs were also observed, consistent with intraindividual and intergenerational reports of mosaic CAG repeats [2,3]and CAG expansion in HD patients [4][5][6][7]. The confirmation of transgene inheritability and development of pathogenic HD phenotype in derived rHD-ESCs reported in this study is a milestone in the pursuit of a transgenic primate model with inherited mutant HTT for development of novel disease biomarkers and therapeutics.…”

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

“…Therefore, both the Hdh neoQ20/null model and its derivative, Hdh d•hyp , by depriving neural structures of adequate levels of Htt during development, may be imitating the severe loss-of-Htt function of the long polyQ expansions associated with JHD. Indeed, the Hdh d•hyp model exhibits several characteristic features of JHD, including reduced body mass index (Tereshchenko et al, 2015), seizures (Cloud et al, 2012), hindlimb stiffness and muscle atrophy (Aubeeluck and Brewer, 2008; Nicolas et al, 2011), extreme gliosis of the globus pallidum (Byers et al, 1973), and cerebellar involvement (Gonzalez-Alegre and Afifi, 2006; Ho et al, 1995). …”

Age-, tissue- and length-dependent bidirectional somatic CAG•CTG repeat instability in an allelic series of R6/2 Huntington disease mice

“…Alleles N 50 repeats are frequently associated with the severe juvenile form of the disorder, although additional increases in inherited allele length have a less dramatic impact on age at onset (Andresen et al, 2007). Nevertheless, there are at least five patients reported who have inherited N200 repeats (Nance et al, 1999;Milunsky et al, 2003;Seneca et al, 2004;Reynolds et al, 2008;Nicolas et al, 2011). The expanded HD allele is highly unstable with a maternal germline mutation frequency of~80% with a~2:1 expansion bias (Duyao et al, 1993).…”