A number sign (#) is used with this entry because of evidence that porphyria-related leukoencephalopathy (LENCEP) 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 encephalopathy (ENCEP; 620704), a more severe disorder with earlier onset.

Heterozygous mutation in the HMBS gene causes acute intermittent porphyria (AIP; 176000), which shows autosomal dominant inheritance with incomplete penetrance.

Porphyria-associated leukoencephalopathy (LENCEP) is an autosomal recessive disorder characterized by the onset of variable and slowly progressive neurologic abnormalities in childhood or adolescence with survival to late adulthood. Features include spastic paraparesis, cerebellar ataxia, peripheral axonal neuropathy, ocular abnormalities, and leukoencephalopathy affecting the deep cerebral white matter on brain imaging. Some individuals have more severe manifestations, such as optic atrophy with progressive visual loss, loss of ambulation, and mild cognitive decline. Laboratory studies show variably increased plasma and urinary levels of delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and uroporphyrin due to decreased HMBS enzyme activity. The severity of the disorder appears to depend on the particular genotype and the variant effects on HMBS enzymatic activity; intrafamilial variability is often observed. The clinical discrepancies may be particularly apparent in individuals with compound heterozygous HMBS variants that have different effects on enzyme function (Stutterd et al., 2021).

Kevelam et al. (2016) reported 3 adult sibs, ranging from 57 to 63 years of age and born of unrelated Dutch parents, who presented with progressive neurologic symptoms in the teenage years (P1) or in early childhood (P2 and P3). P1 had congenital deafness and developed slowly progressive spastic paraplegia as a teen. At age 58 years, he had normal cognition, spastic paraparesis, and distal peripheral neuropathy of the legs, but was able to walk with an aid and was independent for activities of daily living. P2 was a 63-year-old woman with delayed motor development (walking at age 2 years) followed by progressive spastic paraparesis resulting in loss of ambulation and wheelchair dependency at age 4 years. She also had progressive loss of vision due to optic atrophy, pendular nystagmus, convergence palsies, slowly progressive neurologic deterioration with mild cognitive decline, peripheral neuropathy, and cerebellar ataxia and apraxia. At age 63, she was dependent for daily activities, lived in a nursing home, and could participate in simple conversations. P3, a 57-year-old man, walked at 18 months, but never ran. He developed progressive gait abnormalities at 12 years of age and became wheelchair-bound at 35 years. From age 4, he showed progressive visual loss due to optic atrophy. At 57 years, he had spastic paraparesis, distal peripheral neuropathy, cerebellar ataxia and apraxia, almost complete loss of vision, pendular nystagmus, and vertical gaze palsy. He could participate in simple conversations. Brain imaging of all patients showed mildly enlarged lateral ventricles and extensive, confluent, symmetric signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the U-fibers. The white matter abnormalities progressed slowly over time. P2 and P3 had more extensive abnormalities with involvement of the thalami and central pons, as well as cerebellar atrophy. Nerve conduction studies of P2 and P3 suggested an axonal neuropathy, and sural nerve biopsies from P1 and P3 showed progressive loss of thick and thin nerve fibers. PBG and ALA were borderline normal or only mildly elevated. HMBS activity was decreased to about 55 to 67% compared to controls, which the authors noted is similar to heterozygous carriers of HMBS variants.

Stutterd et al. (2021) reported 3 adult patients from 2 unrelated families with a slowly progressive neurologic disease associated with leukoencephalopathy. The disease course was similar to that reported by Kevelam et al. (2016). P1 and P2 were sibs, born of consanguineous Lebanese parents, who had cataracts in early childhood and developed slowly progressive ataxia and dysarthria later in the first decade. At 36 years of age, P1 showed spastic/ataxic paraparesis with walking difficulties and a sensorimotor peripheral neuropathy. Cognition was normal. On questioning, she reported intermittent attacks of abdominal pain and red urine, reminiscent of symptoms of AIP. Her neurologic symptoms progressed and she underwent liver transplantation that resulted in transient improvement for about 12 months. Her 54-year-old brother (P2) had ataxia, lower limb spasticity, mild peripheral neuropathy, and mild cognitive impairment. He became wheelchair-bound and non-verbal after an acute pontine infarction at age 54. P3 was a 45-year-old man, born of unrelated Dutch patients, who had onset of an unsteady gait around 13 years of age after normal early development. He later developed lower limb spasticity, leg weakness, and peripheral numbness associated with abnormal electrophysiologic studies suggesting an axonopathy. Cognition was normal and he remained independent, working as a baker. The mother of P3 had AIP. Brain imaging of all 3 individuals showed extensive, mainly confluent, signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the U-fibers. All 3 patients had thalamic involvement, and 2 had signal abnormalities in the central pons. The white matter abnormalities were slowly progressive. P2 additionally had enlarged ventricles suggestive of cerebral atrophy. Erythrocyte HMBS activity in P1 and P2 was 13 to 18% of normal controls, and urinary ALA and PBG were mildly elevated. HMBS activity was not measured in P3, but he also had only mildly elevated urinary ALA and PBG.

The transmission pattern of LENCEP in the families reported by Kevelam et al. (2016) and Stutterd et al. (2021) was consistent with autosomal recessive inheritance.

In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive LENCEP, Kevelam et al. (2016) identified compound heterozygous missense variants in the HMBS gene: R167Q, 609806.0005 and R225Q, 609806.0047. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Erythrocyte HMBS activity was 55 to 67% of normal in 2 of the affected sibs. Two clinically unaffected sibs carried a heterozygous R225Q variant; erythrocyte HMBS activity in these unaffected sibs was 105% and 83% of normal, respectively, and both had normal urinary ALA and PBG. Kevelam et al. (2016) noted that there is conflicting evidence for the pathogenicity of the R225Q variant and whether the variant impairs HMBS activity. They suggested that R225Q may not cause AIP in the heterozygous state, but may affect HMBS activity when present with another definitively pathogenic mutation, such as R167Q.

In a 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, Stutterd et al. (2021) identified compound heterozygosity for the R225Q and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. Stutterd et al. (2021) noted that the pathogenicity of the R225Q variant had not been conclusively demonstrated and that previous functional studies had yielded conflicting results of the effect of this variant on HMBS enzyme activity. Stutterd et al. (2021) also identified a homozygous missense mutation in the HMBS gene (A84D; 609806.0048) in 2 adult sibs (P1 and P2), born of consanguineous Lebanese parents (family 1), with slowly progressive LENCEP. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity in the affected sibs ranged from 13 to 18% of normal control values. Erythrocyte HMBS activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. Genetic studies of the parents were not performed, but they were noted to be unaffected.