Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient

Abstract

The hypomyelinating leukodystrophies (HMLs) encompass the X-linked Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations and known as the classical form of HML as well as Pelizaeus-Merzbacher-like disease (PMLD) (Online Mendelian Inheritance in Man [OMIM] 608804 and OMIM 260600) due to GJC2 mutations. In addition, mutations in at least 10 other genes are known to cause HMLs. In 2008, an Israeli family with clinical and neuroimaging findings similar to those found in PMD was reported. The patients were found to have a homozygous missense mutation in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60), and the disorder was defined as the autosomal recessive mitochondrial Hsp60 chaperonopathy (MitCHAP-60) disease. We here report the first case of this severe neurodegenerative disease since it was first described. Given the fact that the families carried the same mutation our patient probably belongs to the same extended family as the Israeli family. In conclusion, the MitCHAP-60 disease should be considered as a rare differential diagnosis in HML.

A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy

“…Elevated urine ethylmalonic acid has also been observed in patients in whom homozygosity for the polymorphic c.624G > A variation was found as the only variation in the ACADS gene (Gregersen et al 1998;Pedersen et al 2008). Presence of intermittent increase of urinary ethylmalonic acid excretion has been described in patients with HLD4 (Magen et al 2008;Kusk et al 2016). Earlier studies have shown functional interaction of SCAD with the HSP60 chaperone (Pedersen et al 2003), and therefore elevated levels of ethylmalonic acid, as seen in the current patient, may be B A C Figure 4.…”

“…Brain magnetic resonance imaging (MRI) in these patients reveals diffuse hypomyelination, thin corpus callosum, thin brainstem, and varying degrees of ventricular enlargement. A subset of patients has markedly increased urinary secretion of ethylmalonic acid as well (Magen et al 2008;Bross and Fernandez-Guerra 2016;Kusk et al 2016).…”

“…The human HSPD1 and HSPE1 genes encode the essential mitochondrial HSP60 and HSP10 chaperones, respectively, which form a folding chamber to facilitate protein folding and assembly in the mitochondrial matrix space. Variations in HSPD1 and HSPE1 are implicated in the following neurological diseases (Table 1; Bross and Fernandez-Guerra 2016): (i) homozygosity for the HSP60:p.Asp29Gly variation causes the fatal hypomyelination disorder (HLD4; MitCHAP60 disease; MIM #612233) (Magen et al 2008;Parnas et al 2009;Kusk et al 2016), (ii) heterozygosity for the HSP60:p.Val98Ile variation causes spastic paraplegia (SPG13; MIM #605280) (Hansen et al 2002), (iii) heterozygosity for the HSP10:p.Leu73Phe variation causes a neurological and developmental disorder (Bie et al 2016), and (iv) heterozygosity for the HSP60:p.Leu47Val variation causes hypomyelination disorder (Yamamoto et al 2018). In addition to these genetic variations, another molecular mechanism can lead to HSP10 chaperone deficiency, without involving a genetic alteration in the HSPE1 gene.…”

Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy

“…More recently, a new case of MitCHAP-60 with the homozygous mutation Asp29Gly has been reported [14]. The patient was a two-year-old Syrian boy and showed abnormal myelination and other signs and symptoms mentioned in Table 1.…”

Missense Mutations of Human Hsp60: A Computational Analysis to Unveil Their Pathological Significance

“…For instance, two monogenic disorders have been associated with HSPD1 gene missense mutations than can be deemed Hsp60-genetic chaperonopathies. They are: (1) a dominantly inherited form of spastic paraplegia – SPG13 (OMIM #605280), which is caused by the p.V98I and the p.Q461E missense mutations ( Fontaine et al, 2000 ; Hansen et al, 2002 , 2007 ); and (2) a recessively inherited hypo-myelinating leukodystrophy – HDL4 (OMIM #612233), caused by the p.D29G missense mutation ( Magen et al, 2008 ; Kusk et al, 2016 ). While the clinical and pathological manifestations of these two neurological disorders are well characterized, less is known about the effects of the mutations on protein structure and function and their participation in the mechanisms underpinning the histopathological lesions observed in patients.…”