Genetic Tree of Hereditary Spastic Paraplegia

Unlocking the Mystery of Hereditary Spastic Paraplegia: What You Need to Know About PLA2G6-Associated Neurodegeneration

Lena Kashyap in Health & Wellness December 2025 • 5 min read.

"A New Study Sheds Light on the Genetic Underpinnings and Clinical Variations of a Complex Neurological Disorder"

Hereditary spastic paraplegias (HSPs) are a group of inherited neurological disorders characterized by weakness and spasticity in the lower limbs. These conditions can manifest in different ways, with some individuals experiencing 'pure' HSP, while others develop 'complicated' forms involving additional neurological issues like ataxia, cognitive impairment, or parkinsonism. Identifying the specific genetic cause of HSP is crucial for accurate diagnosis and potential therapeutic strategies.

One of the genes implicated in complex HSP is PLA2G6, which encodes a calcium-independent phospholipase. Mutations in this gene are associated with a spectrum of neurodegenerative disorders collectively known as PLA2G6-associated neurodegeneration (PLAN). These disorders include infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and even some forms of Parkinson's disease. Recent research has also linked PLA2G6 mutations to hereditary spastic paraplegia, expanding the known clinical presentations of PLAN.

A recent study by Koh et al. (2018) delved into the role of PLA2G6 mutations in a cohort of Japanese patients with HSP. By screening 383 families, the researchers aimed to determine the frequency of PLA2G6 mutations and characterize the clinical features associated with these genetic variations. This article breaks down the key findings of this study, offering insights into the genetic landscape of HSP and the diverse ways in which PLA2G6 mutations can manifest.

Decoding PLA2G6 Mutations: What Does This Gene Do?

Genetic Tree of Hereditary Spastic Paraplegia

The PLA2G6 gene provides instructions for making an enzyme called phospholipase A2 group VI. This enzyme plays a critical role in various cellular processes, particularly those involving lipid metabolism and membrane maintenance. It's like a tiny molecular mechanic, ensuring that the fats in our brain cells are properly managed and structured.

When mutations occur in the PLA2G6 gene, the enzyme's function can be disrupted, leading to a buildup of abnormal lipids and cellular dysfunction, especially in the brain. Depending on the specific mutation and its effect on the enzyme's activity, different neurological disorders can arise. This explains why PLA2G6 mutations are linked to such a diverse range of conditions.

Here's a quick breakdown of the different disorders associated with PLA2G6 mutations:

Infantile Neuroaxonal Dystrophy (INAD): A severe, early-onset disorder characterized by rapid neurological decline.
Neurodegeneration with Brain Iron Accumulation (NBIA): A group of disorders where iron accumulates in specific brain regions, leading to progressive neurological damage.
Parkinson's Disease: Some cases of early-onset Parkinson's disease have been linked to PLA2G6 mutations.
Hereditary Spastic Paraplegia (HSP): As the study highlights, PLA2G6 mutations can also cause HSP, particularly complex forms with additional neurological features.

The study by Koh et al. (2018) identified PLA2G6 mutations in four Japanese families with HSP. They found a variety of mutations, including compound heterozygous mutations (where an individual inherits two different mutated copies of the gene) and a homozygous mutation (where an individual inherits the same mutated copy from both parents). The specific mutations identified included c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, c.1187-2 A > G/c.1933C > T, and c.1904G > A/c.1904G > A.

What Does This Mean for Families Affected by HSP?

This study underscores the importance of genetic testing in individuals with HSP, particularly those with complex presentations. Identifying PLA2G6 mutations can provide a more accurate diagnosis, inform prognosis, and potentially guide future therapeutic interventions. While there is currently no cure for PLAN disorders, understanding the underlying genetic cause can help families access appropriate support and management strategies. The research also highlights the diverse clinical spectrum associated with PLA2G6 mutations, suggesting that clinicians should consider this gene in individuals with HSP, even if they present with atypical features. Ultimately, continued research into PLA2G6 and its role in neurodegeneration is essential for developing effective treatments and improving the lives of those affected by these challenging conditions.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1038/s10038-018-0519-7, Alternate LINK

Title: Pla2G6-Associated Neurodegeneration Presenting As A Complicated Form Of Hereditary Spastic Paraplegia

Subject: Genetics (clinical)

Journal: Journal of Human Genetics

Publisher: Springer Science and Business Media LLC

Authors: Kishin Koh, Yuta Ichinose, Hiroyuki Ishiura, Haitian Nan, Jun Mitsui, Junya Takahashi, Wakiro Sato, Yoshiaki Itoh, Kyoko Hoshino, Shoji Tsuji, Yoshihisa Takiyama

Published: 2018-10-09

Everything You Need To Know

What is Hereditary Spastic Paraplegia (HSP), and how does it relate to PLA2G6-associated neurodegeneration (PLAN)?

Hereditary Spastic Paraplegias (HSPs) are a group of inherited neurological disorders primarily characterized by weakness and spasticity in the lower limbs. PLA2G6-associated neurodegeneration (PLAN) represents a spectrum of neurodegenerative disorders caused by mutations in the PLA2G6 gene. The connection is that mutations in PLA2G6 can cause HSP, especially the complex forms, which can include additional neurological issues beyond the typical spasticity and weakness in the legs. This makes understanding the role of the PLA2G6 gene crucial for accurately diagnosing and treating these conditions.

What is the role of the PLA2G6 gene, and how do mutations in it lead to neurodegenerative disorders?

The PLA2G6 gene provides instructions for making an enzyme called phospholipase A2 group VI, which is critical for lipid metabolism and maintaining cell membranes. This enzyme acts like a molecular mechanic, ensuring proper fat management within brain cells. When mutations occur in the PLA2G6 gene, the enzyme's function is disrupted, leading to abnormal lipid buildup and cellular dysfunction, primarily in the brain. The specific mutation and its effect on enzyme activity determine the specific neurological disorder, such as Infantile Neuroaxonal Dystrophy (INAD), Neurodegeneration with Brain Iron Accumulation (NBIA), or even Parkinson's Disease. These disruptions result from the malfunctioning enzyme, hindering its ability to properly manage lipids, leading to cellular damage and various neurological symptoms.

What are the different types of disorders linked to PLA2G6 mutations, and how do they differ?

PLA2G6 mutations are linked to a spectrum of neurodegenerative disorders. These include Infantile Neuroaxonal Dystrophy (INAD), a severe and rapidly progressing disorder that manifests early in life; Neurodegeneration with Brain Iron Accumulation (NBIA), characterized by iron accumulation in brain regions, causing progressive damage; and some cases of Parkinson's Disease, especially those with an early onset. Additionally, PLA2G6 mutations can cause Hereditary Spastic Paraplegia (HSP), particularly in its complex forms. These disorders vary in their specific symptoms, age of onset, and the rate of progression, reflecting the diverse ways in which the PLA2G6 mutations affect the enzyme and subsequent cellular processes.

How did the study by Koh et al. (2018) contribute to our understanding of PLA2G6 mutations and HSP?

The study by Koh et al. (2018) investigated the role of PLA2G6 mutations in a cohort of Japanese patients with HSP. It identified PLA2G6 mutations in four families and determined the prevalence and characterized clinical features. They discovered various mutations, including compound heterozygous and homozygous mutations. The specific mutations identified were c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, c.1187-2 A > G/c.1933C > T, and c.1904G > A/c.1904G > A. These findings highlighted the importance of genetic testing in HSP patients and the diverse clinical presentations associated with PLA2G6 mutations. The study's results underscore the need to consider PLA2G6 in individuals with HSP, even with atypical features, to aid in diagnosis, prognosis, and potentially guide therapeutic interventions.

What are the implications of identifying PLA2G6 mutations for families affected by HSP?

Identifying PLA2G6 mutations in individuals with HSP can lead to more accurate diagnoses, provide insights into prognosis, and potentially influence future therapeutic strategies. This genetic information helps families understand the underlying cause of the condition, which can provide a sense of clarity and direction. While there's currently no cure for PLAN disorders, knowing the genetic cause can connect families with relevant support and management strategies. Furthermore, the research emphasizes the importance of considering PLA2G6 in individuals with HSP, even if their symptoms are not typical, highlighting the diverse clinical spectrum associated with these mutations. This information is essential for families seeking appropriate care and support.