| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.3 | Encephalopathy, porphyria-related | 620704 | Autosomal recessive | 3 | HMBS | 609806 |
A number sign (#) is used with this entry because of evidence that porphyria-related encephalopathy (ENCEP) is caused by homozygous or compound heterozygous mutation in the HMBS gene (609806) on chromosome 11q23.
Biallelic mutation in the HMBS gene also causes porphyria-related leukoencephalopathy (LENCEP; 620711), which shows later onset and a less severe disease course.
Heterozygous mutation in the HMBS gene causes acute intermittent porphyria (AIP; 176000), which shows autosomal dominant inheritance with incomplete penetrance.
Porphyria-related encephalopathy (ENCEP) is an autosomal recessive disorder characterized by the onset of progressive neurologic abnormalities in early infancy. Features include global developmental delay, poor walking or inability to walk, impaired intellectual development, hypotonia, ataxia, dysarthria, spasticity, ocular abnormalities, and peripheral neuropathy. The disease course is usually rapidly progressive and may lead to death in childhood. Laboratory studies show increased plasma and urinary levels of the putatively neurotoxic porphyrin precursors delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and uroporphyrin resulting from deficient HMBS enzymatic activity (Solis et al., 2004).
Beukeveld et al. (1990) reported a Dutch girl with porencephaly, a small brain, and severely impaired psychomotor development apparent from infancy. Laboratory studies showed consistently elevated urinary levels of delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and uroporphyrin. She was in a vegetative state, tube-fed, and had no contact with her environment. She died suddenly at 8 years of age. Her teeth and postmortem liver showed red fluorescence upon exposure to UV light. Her mother had classic symptoms of AIP; although the father never had AIP attacks, blood and urine studies showed that he too was affected. Erythrocyte HMBS activity was not measured in the proband, but was decreased by about 50% in the mother and father.
Llewellyn et al. (1992) reported 2 English sibs who were found to have elevated urinary PBG in infancy. At 18 months of age, the female proband had ataxia, intention tremor, and dysarthria secondary to partial agenesis of the cerebellar vermis, bilateral cataracts, and right optic nerve hypoplasia. She developed febrile seizures at 3 years of age. Laboratory studies showed excessive urinary PBG excretion and significantly decreased erythrocyte HMBS activity (14% of controls). One year later, she had no further seizures or symptoms of acute porphyria. Her younger brother had mildly increased urinary PBG (not as severe as his sister) with similarly decreased HMBS activity (17% of controls). He did not have cataracts, cerebral ultrasound was normal, and he showed normal developmental progress at 18 months of age. The parents did not have clinical symptoms of AIP, but both had slightly decreased HMBS activity (about 50% of normal) and mildly increased urinary PBG excretion, confirming that both had latent AIP. In their table 1, Solis et al. (2004) provided follow-up information on the sibs reported by Llewellyn et al. (1992), who were noted to be 15 and 12 years of age. Both had delayed psychomotor development, ataxia, broad-based gait, dysarthria, dysmetria, ptosis, nystagmus, abnormal smooth pursuit, and coarse facies. The sister had intention tremor, involuntary movements, and cataracts, and the brother had hyperreflexia with clonus and extensor plantar responses. The sister had hypodensities on brain MRI; the brother was not imaged. Solis et al. (2004) stated that the HMBS activity in both sibs was 1.3% of normal. The English sibs reported by Llewellyn et al. (1992) were also referenced by Kevelam et al. (2016), who stated in their table 2 that the sister had died at age 8 years. HMBS activity in the patients was noted to be 14 to 17% of normal values, consistent with the original report.
Hessels et al. (2004) reported a 7-year-old boy, born of consanguineous Turkish parents, who presented soon after birth with hepatosplenomegaly, mild anemia, and hyperbilirubinemia. He had poor overall growth initially and global developmental delay (walked at 2.5 years). He was noted to have yellow-brown teeth and dark red urine associated with increased urinary ALA, porphobilinogen, and uroporphyrin. Further hepta-, hexa-, penta- and copro(I)porphyrins were highly increased in urine. This pattern of porphyrin precursor and metabolite excretion was characteristic of acute intermittent porphyria. The porphobilinogen deaminase activity in red cells was decreased to 2 to 4%. At 7 years of age, he had impaired intellectual development, but could talk and attended a special school. The parents were clinically unaffected, but their erythrocyte HMBS activity was mildly reduced to 73% and 59% of normal controls.
Solis et al. (2004) reported a 13-month-old Spanish boy, born of consanguineous parents, who presented at birth with dark-orange urine. He showed global developmental delay in infancy, with motor delay and inability to walk, no visual fixation or following, and cataracts. Additional features included coarse facial features, mild hepatosplenomegaly, axial hypotonia, dystonic movements, extensor plantar responses, and a mixed sensorimotor peripheral neuropathy with greater sensory involvement. Biochemical studies showed elevated urinary ALA and PBG and deficient erythrocyte HMBS activity (about 1% of controls). The disease course was progressive, and he died of sudden death at 3.3 years of age. Family history revealed a similarly affected older brother who died at 27 months of age with a diagnosis of cerebral palsy. Neurologic and neuroradiologic findings suggested a primary process affecting deep cerebral white matter myelination, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, brainstem, and cerebellum. Thus, the process affected tracts that myelinate in the later postnatal period, but spared the many tracts that myelinate prenatally or shortly after birth. The selective white matter damage was associated with arrest of myelin maturation at the 8- to 10-month milestones, and later with progressive vacuolation/cavitation in the periventricular white matter. The findings were consistent with ALA-mediated neurotoxicity which is manifest postnatally. Solis et al. (2004) noted that if heme deficiency was important in pathogenesis, then it would be expected to cause earlier neuropathologic features. Solis et al. (2004) concluded that the neuropathologic features in this case resulted from postnatal toxic injury, presumably due to the persistent elevation of ALA, PBG, and/or other porphyrin precursors. The findings indicated that the toxic accumulation of porphyrin precursors, rather than heme deficiency, is primarily responsible for acute neurologic attacks in heterozygous AIP.
The transmission pattern of ENCEP in the families reported by Beukeveld et al. (1990), Llewellyn et al. (1992), and Solis et al. (2004) was consistent with autosomal recessive inheritance.
In a Dutch girl with ENCEP originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene (R167Q, 609806.0005 and R173Q, 609806.0006). The parents, who both had symptomatic or latent AIP, were each heterozygous for 1 of the mutations.
In an English brother and sister with ENCEP, Llewellyn et al. (1992) identified compound heterozygous missense mutations in the HMBS gene (R167Q, 609806.0005 and R167W, 609806.0013). The parents, who had latent AIP, were each heterozygous for 1 of the mutations.
In a 7-year-old boy, born of consanguineous Turkish parents, with ENCEP, Hessels et al. (2004) identified a homozygous missense mutation in the HMBS gene (L81P; 609806.0045). Erythrocyte HMBS activity was 2 to 4% of normal. The father and mother, shown to be gene carriers of the same mutation, were asymptomatic with normal urinary porphyrin precursor metabolite excretion, although both had HMBS activity in the reference range for patients with heterozygous AIP.
In a boy, born of consanguineous Spanish parents, with ENCEP, Solis et al. (2004) identified a homozygous missense mutation in the HMBS gene (R167W; 609806.0013). Erythrocyte HMBS activity was about 1% of control values. The clinically unaffected parents were heterozygous for the mutation; HMBS activity in the parents was about 50% of normal controls.
Berger et al. (2020) found that mice homozygous for the R167Q mutation in the Hmbs gene (609806.0005) showed depression-like behavioral abnormalities. RNA-seq analysis of hippocampal tissue from mutant mice showed differentially expressed genes (DEGs) compared to controls. The DEGs were involved in myelination in the CNS and oligodendrocyte development. Mutant mice had fewer hippocampal oligodendrocytes compared to controls and there was evidence of disrupted mitochondrial energy metabolism. Hippocampal neurons in mutant mice showed impaired neuronal cell proliferation and differentiation and aberrant synaptic plasticity. The findings implicated defective myelination as the pathogenic mechanism in the behavioral and neuronal plasticity defects and suggested that mitochondrial dysfunction may play a role.
Berger, S., Stattmann, M., Cicvaric, A., Monje, F. J., Coiro, P., Hotka, M., Ricken, G., Hainfellner, J., Greber-Platzer, S., Yasuda, M., Desnick, R. J., Pollak, D. D. Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria. Acta Neuropath. Commun. 8: 38, 2020. [PubMed: 32197664] [Full Text: https://doi.org/10.1186/s40478-020-00910-z]
Beukeveld, G. J. J., Wolthers, B. G., Nordmann, Y., Deybach, J. C., Grandchamp, B., Wadman, S. K. A retrospective study of a patient with homozygous form of acute intermittent porphyria. J. Inherit. Metab. Dis. 13: 673-683, 1990. [PubMed: 2246851] [Full Text: https://doi.org/10.1007/BF01799566]
Hessels, J., Voortman, G., van der Wagen, A., van der Elzen, C., Scheffer, H., Zuijderhoudt, F. M. J. Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors. J. Inherit. Metab. Dis. 27: 19-27, 2004. [PubMed: 14970743] [Full Text: https://doi.org/10.1023/B:BOLI.0000016613.75677.05]
Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. Acute intermittent porphyria-related leukoencephalopathy. Neurology 87: 1258-1265, 2016. [PubMed: 27558376] [Full Text: https://doi.org/10.1212/WNL.0000000000003129]
Llewellyn, D. H., Smyth, S. J., Elder, G. H., Hutchesson, A. C., Rattenbury, J. M., Smith, M. F. Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. Hum. Genet. 89: 97-98, 1992. [PubMed: 1577472] [Full Text: https://doi.org/10.1007/BF00207051]
Picat, C., Delfau, M. H., de Rooij, F. W. M., Beukeveld, G. J. J., Wolthers, B. G., Wadman, S. K., Nordmann, Y., Grandchamp, B. Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria. J. Inherit. Metab. Dis. 13: 684-686, 1990. [PubMed: 2246852] [Full Text: https://doi.org/10.1007/BF01799567]
Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch. Neurol. 61: 1764-1770, 2004. [PubMed: 15534187] [Full Text: https://doi.org/10.1001/archneur.61.11.1764]