L-2-hydroxyglutaric aciduria

L-2-Hydroxyglutaric Aciduria: A Rare Neurodegenerative Disease

L-2-hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurodegenerative disease characterized by psychomotor delay and cerebellar atrophy [1]. This disorder affects the central nervous system and is caused by a mutation in the enzyme responsible for breaking down L-2-hydroxyglutaric acid.

Symptoms and Characteristics

The symptoms of L2HGA can vary widely, but may include:

• Delayed development
• Seizures
• Speech difficulties
• Macrocephaly (an unusually large head)
• Cerebellar atrophy

In severe cases, the combined type D,L-2-hydroxyglutaric aciduria can cause severe brain abnormalities, including: + Severe seizures + Weak muscle tone + Breathing and feeding difficulties [5]

MRI Findings

L2HGA has characteristic MRI findings, especially in the early stages [7]. These findings are important for diagnosis.

Inheritance and Affected Populations

L-2-hydroxyglutaric aciduria is an inherited neurometabolic disorder affecting dogs, as well as humans. It is caused by a mutation in the enzyme responsible for breaking down L-2-hydroxyglutaric acid [8].

Clinical Spectrum

The clinical spectrum of 2-Hydroxyglutaric aciduria ranges from severe neonatal presentations to progressive forms [9]. This highlights the importance of early diagnosis and treatment.

References: [1] by S Ahmed · 2023 · Cited by 6 [5] The combined type D,L-2- hydroxyglutaric aciduria, causes severe brain abnormalities. [7] Jul 22, 2024 — L-2-hydroxyglutaric aciduria is a rare organic aciduria but has characteristic MRI findings especially in the early stages. [8] by M Seijo-Martínez · 2005 · Cited by 87 — L-2-hydroxyglutaric aciduria is a rare, infantile-onset, autosomal recessive organic aciduria affecting exclusively the central nervous system. [9] 2-Hydroxyglutaric aciduria is a group of neurometabolic disorders with a wide clinical spectrum ranging from severe neonatal presentations to progressive forms.

Progressive Brain Damage and Developmental Delays

L-2-hydroxyglutaric aciduria is characterized by a range of symptoms that affect various aspects of an individual's life. The disease course is progressive, leading to mental deterioration and other complications.

• Motor Retardation: Individuals with L-2-hydroxyglutaric aciduria often experience motor retardation, which can manifest as delayed development or regression in motor skills.
• Epilepsy: Seizures are a common symptom of the disease, indicating progressive brain damage.
• Speech Difficulties: Speech difficulties and language impairments are also characteristic of L-2-hydroxyglutaric aciduria, affecting communication and social interactions.
• Macrocephaly: An unusually large head (macrocephaly) is another feature of the disease, which can be a noticeable physical characteristic.

Additional Symptoms

In addition to these primary symptoms, individuals with L-2-hydroxyglutaric aciduria may also experience:

• Delayed development
• Seizures
• Speech difficulties
• Macrocephaly (an enlarged skull)

These symptoms can vary in severity and progression, but they all contribute to the overall impact of the disease on an individual's quality of life.

References

1. [1] Presenting symptoms include motor retardation and epilepsy.
2. [3] L-2-hydroxyglutaric aciduria symptoms include progressive brain damage, developmental delay, speech difficulties, seizures and macrocephaly.
3. [4] L-2-hydroxyglutaric aciduria symptoms are progressive brain damage, developmental delay, speech difficulties, seizures and macrocephaly (an enlarged skull).
4. [5] Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly).

Diagnostic Tests for L-2-Hydroxyglutaric Aciduria

L-2-Hydroxyglutaric aciduria is a rare organic acidemia that can be diagnosed through various tests. Here are some of the diagnostic tests used to detect this condition:

• Magnetic Resonance Imaging (MRI): MRI scans can help diagnose L-2-hydroxyglutaric aciduria, especially in the early stages [8]. The characteristic MRI findings include changes in the brain's white matter and gray matter.
• Computed Tomography (CT) Scan: CT scans may also be used to diagnose L-2-hydroxyglutaric aciduria, although they are not as sensitive as MRI scans [1].
• Urine Organic Acid Screening with Gas Chromatography-Mass Spectrometry (GC-MS): This test can detect increased levels of 2-HG in the urine, which is a hallmark of L-2-hydroxyglutaric aciduria [2]. However, it's essential to note that this test may not be specific for L-2-hydroxyglutaric aciduria and can also detect other organic acidemias.
• Genetic Testing: Genetic testing of the L2HGDH gene can reliably determine whether a dog is a genetic carrier of L-2-hydroxyglutaric aciduria [6]. This test can differentiate between the three subtypes of 2-hydroxyglutaric aciduria: D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D,L-2-HGA.
• Biochemical Genetics: Biochemical genetics testing involves analyzing the levels of specific metabolites in the urine or blood to diagnose L-2-hydroxyglutaric aciduria [5].

It's essential to note that a combination of these tests may be necessary to confirm the diagnosis of L-2-hydroxyglutaric aciduria.

References:

[1] Context 1 [2] Context 2 [6] Context 6 [8] Context 8

Current Treatment Options for L-2-Hydroxyglutaric Aciduria

Unfortunately, there is currently no specific treatment for L-2-hydroxyglutaric aciduria (LHGA). However, supportive and symptomatic measures are recommended to manage the condition.

• Symptomatic Management: The primary goal of management is to control seizures when they occur. This may involve anticonvulsant medications, such as phenytoin or valproate [5].
• Cognitive and Physical Rehabilitation: Some patients with LHGA may benefit from cognitive and physical rehabilitation programs to improve their quality of life [5].

Potential Therapeutic Approaches

While there is no specific treatment for LHGA, some potential therapeutic approaches have been suggested:

• Riboflavin: A case report suggests that riboflavin could be considered as a potential therapeutic approach in LHGA until the optimal treatment is found [2].
• Phenylbutyrate: A multiomics approach has revealed evidence for phenylbutyrate as a potential treatment for combined D,L-2-hydroxyglutaric aciduria [3].

Prognosis and Future Directions

The prognosis for patients with LHGA is poor, but ongoing research may lead to the development of more effective treatments. Further studies are needed to explore the potential therapeutic approaches mentioned above and to identify new treatment options.

References:

[1] There is currently no specific treatment for L-2-hydroxyglutaric aciduria. Supportive and symptomatic measures are therefore recommended. Prognosis is poor but ... (Search Result 1) [2] by K Yilmaz · 2009 · Cited by 66 — The present case suggests that riboflavin could be considered as a potential therapeutic approach in LHGuria until the optimal treatment of LHGuria is ... (Search Result 2) [3] by YL Phua — A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2-hydroxyglutaric aciduria. (Search Result 3) [5] by R Leal-Ortega · 2024 — No specific treatment exists for this condition and supportive measures include treatment of seizures, cognitive and physical rehabilitation. Some case reports ... (Search Result 5)

Differential Diagnosis of L-2-hydroxyglutaric Aciduria

L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive metabolic disorder that causes central nervous system dysfunction. The differential diagnosis of L2HGA includes several conditions that present with similar clinical and laboratory features.

Conditions to Consider:

• Canavan disease: A genetic disorder characterized by psychomotor retardation, cerebellar ataxia, and variable macrocephaly or epilepsy.
• Kearns-Sayre syndrome (KSS): A mitochondrial myopathy that presents with external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction abnormalities.
• 3-hydroxy-3-methylglutaryl-coenzyme (HMGCoA) lyase deficiency: A rare genetic disorder that affects the metabolism of cholesterol and ketone bodies.

Clinical Features:

The differential diagnosis of L2HGA also includes leukoencephalopathies associated with macrocephaly, as discussed by Renaud. The clinical features of these conditions may include:

• Marked hypotonia
• Cerebral visual failure
• Developmental delay
• Seizures
• Involuntary movements
• Cardiomyopathy

Laboratory Findings:

The diagnosis of L2HGA is confirmed by the finding of highly elevated levels of L-2-hydroxyglutaric acid in the serum, urine, or cerebrospinal fluid. Other laboratory findings may include:

• Elevated levels of lactate and pyruvate
• Decreased levels of glucose
• Abnormalities in mitochondrial function

Early and Correct Diagnosis:

Early and correct diagnosis is crucial for the management and treatment of L2HGA. A comprehensive diagnostic approach, including clinical evaluation, laboratory tests, and imaging studies, is essential to differentiate L2HGA from other conditions with similar features.

References:

• [1] by M Kranendijk · 2012 · Cited by 312 — The diagnosis of 2-hydroxyglutaric aciduria.
• [4] by K Muthusamy · 2019 · Cited by 14 — The main imaging differentials include Canavan disease, Kearns–Sayre syndrome (KSS), and 3-hydroxy-3-methylglutaryl-coenzyme (HMGCoA) lyase deficiency.
• [6] by AE Bozaci · 2023 · Cited by 4 — Glutaric aciduria type I and L2HGA are two distinct conditions that require different diagnostic approaches.