Differential Diagnosis of Huntington's Disease-like Syndromes
Differential Diagnosis of Huntington's Disease-like Syndromes
The rate of progression of HD can vary considerably across subjects, being, at least in part, related to age of onset and length of trinucleotide-repeat expansion. HD-like syndromes with adult onset may vary in their speed of progression. Importantly, some conditions may progress more rapidly. Among the latter, HDL1, a very rare autosomal dominant prion disease with onset in early adulthood (third–fourth decades), should be kept in account. HDL1 is caused by a 192-nucleotide insertion in a region of the prion protein (PRNP) gene coding for an octapeptide-repeat. HDL1 is recognised as the fourth genetic prion disease phenotype, although not associated typically with spongiform degeneration pathology, but with atrophy and prion deposition within basal ganglia, frontal and temporal lobes, and cerebellar cortex. Although this condition progresses more slowly than other prion diseases, case series reported that most subjects survive between 1 and 10 years from onset. Patients develop prominent personality changes, cognitive decline, chorea, rigidity, limb and truncal ataxia, dysarthria and seizures. It is useful to remind that chorea may be a feature also of the most common prion disease, that is, Creutzfeldt–Jakob disease. Other forms characterised by higher speed of progression are HDL2, relentlessly leading to death within 10–20 years, and DRPLA, generally leading to death within 10–15 years.
Like juvenile HD, HD-like syndromes with earlier onset progress rapidly. An outstanding exception is benign hereditary chorea (BHC), which, unlike other HD-like syndromes with onset in the first 2 decades, is characterised by a non-progressive or very slowly progressive course dominated by chorea. BHC is now considered a genetically heterogeneous spectrum, first described as an early-onset form of chorea not associated with intellectual deterioration. It is suspected in cases of focal or generalised chorea with autosomal dominant inheritance, and is often described as socially embarrassing (online supplementary video 4). Disease onset occurs in early infancy. A relevant proportion of these cases bear mutations in the NKX2-1 gene encoding for thyroid transcription factor-1 (TITF-1), which is a very important transcription factor involved in the organogenesis of the brain, thyroid and lungs. An allelic disorder to BHC presents with a more severe phenotype characterised by choreoathetosis, congenital hypothyroidism and neonatal respiratory distress, also referred to as 'brain-thyroid-lung syndrome', and therefore very different from HD. These cases have also been associated with loss of TITF-1-mediated striatal interneurons. Given its more benign outcome, it is very important to distinguish BHC from HD, although not always easy, due to its variable expression. Less frequently than chorea, these patients can manifest intention tremor, dysarthria, gait impairment and exceptionally even psychosis, psychomotor developmental problems and short stature. Albeit usually non-progressive, the phenotype of BHC might change with time, shifting from chorea to myoclonus and dystonia. Reduced striatal volumes on volumetric studies have also been reported. However, genetic heterogeneity has been observed, with two Japanese families expressing a similar phenotype but with onset between ages 40 and 66, and for this reason resembling adult-onset HD; these subjects, however, lacked cognitive impairment and exhibited an association with a different locus on chromosome 8q. This picture has been named BHC 2, and a postmortem report in one of these patients surprisingly showed pathological changes remarkably similar to those typical of progressive supranuclear palsy (neurofibrillary tangles and tufted astrocytes immunoreactive for four-repeat isoforms of τ).
Speed of Progression
The rate of progression of HD can vary considerably across subjects, being, at least in part, related to age of onset and length of trinucleotide-repeat expansion. HD-like syndromes with adult onset may vary in their speed of progression. Importantly, some conditions may progress more rapidly. Among the latter, HDL1, a very rare autosomal dominant prion disease with onset in early adulthood (third–fourth decades), should be kept in account. HDL1 is caused by a 192-nucleotide insertion in a region of the prion protein (PRNP) gene coding for an octapeptide-repeat. HDL1 is recognised as the fourth genetic prion disease phenotype, although not associated typically with spongiform degeneration pathology, but with atrophy and prion deposition within basal ganglia, frontal and temporal lobes, and cerebellar cortex. Although this condition progresses more slowly than other prion diseases, case series reported that most subjects survive between 1 and 10 years from onset. Patients develop prominent personality changes, cognitive decline, chorea, rigidity, limb and truncal ataxia, dysarthria and seizures. It is useful to remind that chorea may be a feature also of the most common prion disease, that is, Creutzfeldt–Jakob disease. Other forms characterised by higher speed of progression are HDL2, relentlessly leading to death within 10–20 years, and DRPLA, generally leading to death within 10–15 years.
Like juvenile HD, HD-like syndromes with earlier onset progress rapidly. An outstanding exception is benign hereditary chorea (BHC), which, unlike other HD-like syndromes with onset in the first 2 decades, is characterised by a non-progressive or very slowly progressive course dominated by chorea. BHC is now considered a genetically heterogeneous spectrum, first described as an early-onset form of chorea not associated with intellectual deterioration. It is suspected in cases of focal or generalised chorea with autosomal dominant inheritance, and is often described as socially embarrassing (online supplementary video 4). Disease onset occurs in early infancy. A relevant proportion of these cases bear mutations in the NKX2-1 gene encoding for thyroid transcription factor-1 (TITF-1), which is a very important transcription factor involved in the organogenesis of the brain, thyroid and lungs. An allelic disorder to BHC presents with a more severe phenotype characterised by choreoathetosis, congenital hypothyroidism and neonatal respiratory distress, also referred to as 'brain-thyroid-lung syndrome', and therefore very different from HD. These cases have also been associated with loss of TITF-1-mediated striatal interneurons. Given its more benign outcome, it is very important to distinguish BHC from HD, although not always easy, due to its variable expression. Less frequently than chorea, these patients can manifest intention tremor, dysarthria, gait impairment and exceptionally even psychosis, psychomotor developmental problems and short stature. Albeit usually non-progressive, the phenotype of BHC might change with time, shifting from chorea to myoclonus and dystonia. Reduced striatal volumes on volumetric studies have also been reported. However, genetic heterogeneity has been observed, with two Japanese families expressing a similar phenotype but with onset between ages 40 and 66, and for this reason resembling adult-onset HD; these subjects, however, lacked cognitive impairment and exhibited an association with a different locus on chromosome 8q. This picture has been named BHC 2, and a postmortem report in one of these patients surprisingly showed pathological changes remarkably similar to those typical of progressive supranuclear palsy (neurofibrillary tangles and tufted astrocytes immunoreactive for four-repeat isoforms of τ).