Guidelines on Hereditary Leukodystrophies
Mitochondrial Hsp60 chaperonopathy (MitCHAP60; HLD4, OMIM #612233)
Disease description: Mitochondrial Hsp60 chaperonopathy is a form of dysmyelination of the central nervous system caused by a mutation in the HSPD1 gene encoding the Hsp60 protein, a mitochondrial chaperone (heat shock protein). It exhibits autosomal recessive inheritance. Spasticity, developmental delay, and regression occur from early in infancy and childhood; in severe cases, death occurs by 1–2 years of age. There is currently no effective treatment, and only symptomatic care is provided.
1. Overview
Definition
Mitochondrial Hsp60 chaperonopathy is a form of congenital cerebral leukodystrophy caused by an abnormality of the Hsp60 protein, a mitochondrial chaperone (one of the main constituents of the protein architecture in the mitochondrial matrix). The causative gene is HSPD1, the gene located on 2q33.1 that encodes Hsp60 and exhibits autosomal recessive inheritance.
Epidemiology
The only cases reported to date are in an extended Bedouin family in Israel that engaged in repeated consanguineous marriage and a Syrian patient.1)2)
Etiology and pathophysiology
Hsp60 conjugates with Hsp10 and assists with the folding architecture of proteins taken up by mitochondria using the energy released by the hydrolysis of adenosine triphosphate. It also corrects the architecture of proteins that have folded incorrectly under conditions of oxidative stress. Hsp60 protein abnormalities cause the accumulation of incorrectly folded proteins in the mitochondria and increase their rate of apoptosis, causing this condition to develop.
Clinical symptoms
Hypotonia, nystagmus, and delayed psychomotor development are noticeable within 3 months of age. Severe spasticity, developmental delay, and regression (inability to hold up the head) are evident from early infancy. Epilepsy is also present in around half of cases. Difficulty eating leads to malnutrition and impaired growth. Most patients die before 20 years of age of aspiration pneumonia or sudden unexplained death. Fever results in apnea or tachypnea; in severe cases, patients may die by 1–2 years of age. Those who survive past age 2 years exhibit progressive spastic palsy and limb contracture (the longest-surviving patient was 14 years). Intra- and interfamilial variations of the phenotype is observed.
Imaging and other investigations
MRI shows diffuse hyperintensity of the cerebral and cerebellar white matter on T2-weighted imaging, with almost no evident myelination. Thinning of the corpus callosum, ventricular enlargement, and atrophy of the brainstem and cerebellum are also present. The myo-inositol/creatinine ratio is elevated on magnetic resonance spectroscopy, reflecting glial proliferation. Wave I prolongation and the loss of waves II–V is evident in the auditory brainstem response. Lactic acid and pyruvic acid are not usually elevated in the blood and cerebrospinal fluid.
Genetic diagnosis
The genetic diagnosis is performed by the DNA sequencing of HSPD1, the gene encoding Hsp60. In all families reported to date, the disease occurs due to a homozygous D29G mutation, and heterozygous carriers are asymptomatic. Spastic paraplegia type 13 is caused by another HSPD1 mutation that exhibits autosomal dominant inheritance (SPG13; OMIM #605280).3)
2. Treatment and care
At this point, only symptomatic therapy is provided.
3. Diet and nutrition
Decreased swallowing ability due to hypotonia causes difficulty eating, which may result in underdevelopment and malnutrition. Nasogastric tube feeding is often required.
4. Prognosis
The prognosis varies widely, with some patients dying before age 2 years and the longest surviving patient living until age 14 years.
5. Differential diagnosis
The most important differential diagnoses are Pelizaeus-Merzbacher disease and Pelizaeus-Merzbacher–like disease associated with the PLP1 and GJC2 genes.
6. Recent topics
About half of cases involve elevated urinary ethylmalonic acid and methylsuccinic acid. Urinary ethylmalonic acid is a marker of short-chain acyl-CoA dehydrogenase (SCAD) deficiency, suggesting that there may be an association between decreased Hsp60 protein function and abnormal SCAD protein synthesis.
References
(Unless otherwise noted at the end, all are evidence level 6.)
- Daniella M, Costa G, Petter Bross, et al. Mitochondrial Hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet 2008; 83: 30-42.
- Kusk MS, Damgaard B, Risom L, et al. Hypomyelinating leukodystrophy due to HSPD1 mutations: a new patient. Neuropediatrics 2016; 47: 332-335.
- Hansen JJ1, Dürr A, Cournu-Rebeix I, et al. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 2002; 70: 1328-1332.
