Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment

Neurogenetics. 2022 Jul;23(3):167-177. doi: 10.1007/s10048-022-00688-3. Epub 2022 Apr 9.


The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

Keywords: Genetic metabolic disorder; Hereditary spastic paraplegia; Inborn error metabolism; Spastic paraplegia; Treatable diseases.

Publication types

  • Review

MeSH terms

  • Homocystinuria*
  • Humans
  • Muscle Spasticity
  • Quality of Life
  • Spastic Paraplegia, Hereditary* / diagnosis
  • Spastic Paraplegia, Hereditary* / genetics
  • Spastic Paraplegia, Hereditary* / metabolism
  • Vitamin B 12 Deficiency / congenital

Supplementary concepts

  • Methylmalonic acidemia with homocystinuria