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Background <p>Heterozygous mutations of the hydroxymethylbilane synthase gene can lead to acute intermittent porphyria, with episodic abdominal pain and neuropsychiatric symptoms. The heme precursors 5-aminolevulinic acid and porphobilinogen accumulate due to enzyme deficiency. Case reports of biallelic pathogenic hydroxymethylbilane synthase gene variants are very rare.</p> Methods <p>This case report presents a severely affected boy with biallelic pathogenic hydroxymethylbilane synthase gene variants and includes literature overview of other case reports and experimental data.</p> Case presentation <p>At the age of 2 years, a Caucasian boy with pathologic psychomotor development was diagnosed with biallelic pathogenic hydroxymethylbilane synthase gene variants. As in previous case reports, he did not exhibit symptoms of acute intermittent porphyria, but progressive cystic leukoencephalopathy and neurological decay. In his urine, 5-aminolevulinic acid and porphobilinogen were markedly elevated, but in cerebrospinal fluid just porphobilinogen.</p> Literature review <p>Data of human and animal studies indicate that neurologic symptoms of acute intermittent porphyria are caused by 5-aminolevulinic acid, which episodically accumulates from hepatic origin. Here, as long-term treatment, the inhibition of hepatic heme synthesis with the small interfering RNA givosiran has proven to be effective. In case of biallelic pathogenic hydroxymethylbilane synthase gene variants, the heme precursors 5-aminolevulinic acid or porphobilinogen originating from the liver or central nervous system could be causative, and absolute heme deficiency in the central nervous system is another hypothesis. However, parenterally administered heme, which is effective in acute intermittent porphyria, does not reach the central nervous system. In one case of biallelic pathogenic hydroxymethylbilane synthase gene variants, a liver transplantation did not lead to long-term benefit.</p> Conclusion <p>For differential diagnosis of cystic leukoencephalopathy, biallelic pathogenic hydroxymethylbilane synthase gene variants should be considered. Its pathogenesis probably differentiates from acute intermittent porphyria. To date, there is no promising therapeutic approach.</p>

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Biallelic pathogenic hydroxymethylbilane synthase gene variants of a neurodegenerative disorder with progressive cystic leukoencephalopathy: a case report

  • 期刊论文

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  • 发表日期：

    2026年2月23日

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  • Gabriel Schacht,
  • Miriam Elbracht,
  • Anna-Elisabeth Minder,
  • Thomas Stauch,
  • Arzu Stoppe,
  • Eva Lausberg,
  • Martin Häusler

摘要

Background

Heterozygous mutations of the hydroxymethylbilane synthase gene can lead to acute intermittent porphyria, with episodic abdominal pain and neuropsychiatric symptoms. The heme precursors 5-aminolevulinic acid and porphobilinogen accumulate due to enzyme deficiency. Case reports of biallelic pathogenic hydroxymethylbilane synthase gene variants are very rare.

Methods

This case report presents a severely affected boy with biallelic pathogenic hydroxymethylbilane synthase gene variants and includes literature overview of other case reports and experimental data.

Case presentation

At the age of 2 years, a Caucasian boy with pathologic psychomotor development was diagnosed with biallelic pathogenic hydroxymethylbilane synthase gene variants. As in previous case reports, he did not exhibit symptoms of acute intermittent porphyria, but progressive cystic leukoencephalopathy and neurological decay. In his urine, 5-aminolevulinic acid and porphobilinogen were markedly elevated, but in cerebrospinal fluid just porphobilinogen.

Literature review

Data of human and animal studies indicate that neurologic symptoms of acute intermittent porphyria are caused by 5-aminolevulinic acid, which episodically accumulates from hepatic origin. Here, as long-term treatment, the inhibition of hepatic heme synthesis with the small interfering RNA givosiran has proven to be effective. In case of biallelic pathogenic hydroxymethylbilane synthase gene variants, the heme precursors 5-aminolevulinic acid or porphobilinogen originating from the liver or central nervous system could be causative, and absolute heme deficiency in the central nervous system is another hypothesis. However, parenterally administered heme, which is effective in acute intermittent porphyria, does not reach the central nervous system. In one case of biallelic pathogenic hydroxymethylbilane synthase gene variants, a liver transplantation did not lead to long-term benefit.

Conclusion

For differential diagnosis of cystic leukoencephalopathy, biallelic pathogenic hydroxymethylbilane synthase gene variants should be considered. Its pathogenesis probably differentiates from acute intermittent porphyria. To date, there is no promising therapeutic approach.