MSUD: Maple syrup urine disease

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 MSUD: Maple syrup urine disease

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by a defect in the metabolism of branched-chain amino acids (BCAAs), leading to their accumulation in the body.

1. Cause and Etiology:

Maple syrup urine disease is caused by a genetic mutation in one of the genes encoding enzymes involved in the branched-chain alpha-keto acid dehydrogenase (BCKD) complex. This enzyme is responsible for the catabolism (breakdown) of branched-chain amino acids (BCAAs): leucine, isoleucine, and valine.

The specific genes involved in MSUD include:

  • BCKDHA (for the E1 alpha subunit of BCKD)
  • BCKDHB (for the E1 beta subunit of BCKD)
  • DBT (for the E2 subunit of BCKD)
  • DLD (for the E3 subunit of BCKD)

The inherited mutations lead to a reduced or absent activity of the BCKD enzyme complex, causing a toxic buildup of BCAAs and their corresponding keto acids, which affect various organ systems, especially the brain.

2. Pathophysiology:

In MSUD, the branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) cannot be properly metabolized due to defective enzyme activity. This leads to their accumulation in the blood and tissues, which is toxic, particularly to the central nervous system (CNS).

  • The most notable effect is on leucine: elevated levels of leucine, along with its corresponding keto acids, are thought to impair neuronal function by interfering with neurotransmitter metabolism, brain metabolism, and energy production.
  • Hyperammonemia can also occur as a result of defective amino acid catabolism.
  • Brain edema and neuronal damage can occur, leading to cognitive and neurological issues.

3. Epidemiology:

  • MSUD is autosomal recessive, meaning that an individual must inherit two defective copies of the gene (one from each parent) to develop the disease.
  • The incidence varies by population. In general, the incidence is estimated to be 1 in 185,000 to 250,000 live births globally. However, in certain populations, such as the Old Order Amish (1 in 176 live births) or French Canadians (1 in 25,000), the incidence is much higher due to founder effects and genetic isolation.
  • There are no gender differences in terms of incidence, and the disease affects all ethnic groups.

4. Clinical Presentation:

MSUD typically presents in the neonatal period, although the age of onset can vary depending on the type and severity of the disorder. The classic form, which is the most severe, generally presents within the first few days of life.

Key clinical features:

  • Distinctive odor: The urine of affected individuals has a sweet, maple syrup-like odor, due to the presence of branched-chain amino acids and their metabolites.
  • Poor feeding: Newborns often have difficulty feeding and may show signs of vomiting.
  • Lethargy and poor muscle tone (hypotonia).
  • Ketoacidosis: Metabolic acidosis can be present due to the accumulation of branched-chain keto acids.
  • Neurological symptoms: These may include seizures, developmental delay, and progressive cognitive impairment if left untreated.
  • Coma and death: In severe cases, if not treated promptly, MSUD can lead to encephalopathy, coma, and death during the first few months of life.

5. Imaging Features:

Imaging can show characteristic findings related to the effects of MSUD on the brain:

  • MRI of the brain in affected infants often reveals cerebral edema and changes in white matter, especially in the basal ganglia.
  • Basal ganglia involvement can result in increased signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, which is thought to be due to neuronal swelling and damage.

6. Treatment:

The treatment of MSUD involves dietary management and sometimes medical interventions to reduce the accumulation of toxic metabolites.

  • Dietary management: The cornerstone of treatment involves restricting BCAAs (leucine, isoleucine, and valine) in the diet. A special low-protein diet and the use of BCAA-free amino acid supplements are essential to prevent toxic accumulation.
  • Emergency management: In an acute metabolic crisis, immediate intervention is necessary:
    • Intravenous (IV) glucose and fluids to prevent catabolism and to manage hypoglycemia.
    • Dialysis may be required to remove excess branched-chain amino acids and keto acids in cases of severe metabolic decompensation.
    • Thiamine supplementation: In some cases, thiamine can enhance residual enzyme activity, although this is not a cure.
  • Liver transplantation: For patients who do not respond well to dietary management, or those with severe, progressive forms of MSUD, a liver transplant may be considered, as the liver is the primary site of BCAA metabolism.

7. Prognosis:

  • If diagnosed early and treated appropriately, the prognosis can be significantly improved. Early dietary intervention and constant monitoring of BCAA levels can allow for normal growth and development in many cases.
  • Long-term management: Ongoing lifelong dietary restrictions and close monitoring are essential to prevent metabolic crises and neurological complications.
  • Without treatment, MSUD can lead to severe neurological damage, intellectual disability, and early death, typically in infancy or early childhood.
  • Neurological outcomes: Some patients may experience intellectual disability, developmental delays, and motor impairments, especially if diagnosed late or during a metabolic crisis.

Maple syrup urine disease is a life-threatening metabolic disorder caused by defective BCKD enzyme activity, leading to the accumulation of branched-chain amino acids. Early diagnosis and strict dietary management are critical for improving outcomes. Without treatment, the condition can lead to severe neurological deficits or death. Regular monitoring, including urine and blood tests, is essential for managing the disease throughout the lifespan of the patient.

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Case study: 10-Day-Old Male Neonate with Decreased Activity and Muscle Tone 

Maple Syrup Urine Disease (MSUD)

History and Imaging Findings

  1. A 10-day-old male neonate presented with decreased activity and hypotonia beginning approximately 48 hours after birth, along with diminished sucking ability.

  2. The symptoms appeared to progress gradually over time.

  3. The pregnancy history was unremarkable. The infant was delivered at full term via spontaneous vaginal delivery and cried immediately after birth.

  4. The postnatal period was uneventful.

  5. There was no fever, seizure activity, or jaundice of the eyes.

  6. A complete blood count showed no evidence of infection, and cranial ultrasonography was unremarkable.

  7. The patient subsequently underwent brain MRI.

  8. Selected axial T1-weighted images are provided below.


Quiz 1:
Where is the most notable abnormality located?
(1) Scalp
(2) Sella
(3) Cerebellar white matter
(4) Fourth ventricle

Explanation:
A low signal intensity is observed in the cerebellar white matter. The fourth ventricle appears normal.

Additional MR Imaging Sequences

  1. The primary abnormal findings are most clearly visible on diffusion-weighted imaging (DWI).

  2. A series of contiguous axial DWI images from the brainstem to the semioval center is shown below.

  3. True diffusion restriction was confirmed on the apparent diffusion coefficient (ADC) images (not provided).

Quiz 2:

  1. The main findings are bilateral and symmetrical.
    (1) True
    (2) False

Explanation:
Restricted diffusion, primarily involving the white matter, appears bilaterally symmetrical.

  1. The areas of diffusion restriction are due to acute ischemic changes.
    (1) True
    (2) False

Explanation:
The restricted diffusion areas result from white matter edema, not acute ischemia.

  1. Which of the following brain regions are affected by this abnormality?
    (1) Cerebral peduncles
    (2) Optic tracts
    (3) Perirolandic white matter
    (4) Internal capsules
    (5) All of the above

Explanation:
Abnormal signal intensities involve the cerebellar white matter, medulla, pons, midbrain (cerebral peduncles), caudate nucleus, lentiform nucleus, thalami, internal capsules, optic tracts, and periventricular white matter.

  1. Which of the following should be included in the differential diagnosis?
    (1) Nonketotic hyperglycinemia
    (2) Maple syrup urine disease
    (3) Canavan disease
    (4) Hypoxic-ischemic encephalopathy
    (5) All of the above

  1. Which test is necessary to confirm the diagnosis?
    (1) Otoacoustic emission (OAE) test
    (2) Guthrie test
    (3) Barlow test
    (4) Ortolani test
    (5) None of the above

Newborn Screening (NBS) Results

  1. The patient underwent a newborn screening test (NBS), also known as a heel prick test or Guthrie test. The results became available approximately two days after the brain MRI was performed.

  2. The table below shows the patient’s NBS results.

Quiz 3:
Considering the MRI findings and NBS results, what is the most likely diagnosis?
(1) Nonketotic hyperglycinemia
(2) Maple syrup urine disease (MSUD)
(3) Canavan disease
(4) Hypoxic-ischaemic encephalopathy
(5) None of the above

Explanation:
The newborn screening (NBS) showed markedly elevated levels of branched-chain amino acids, confirming the diagnosis of maple syrup urine disease (MSUD), which is also supported by MRI findings.

Findings and Diagnosis

MRI Findings:

Axial T1-weighted images:
Subtle low signal intensity is observed in the cerebellar white matter. This finding is bilaterally symmetrical.

Diffusion-weighted imaging (DWI):
Bilateral symmetrical diffusion restriction is observed in the cerebellar white matter, medulla, pons, midbrain (cerebral peduncles), lentiform nuclei, thalami, internal capsules, optic tracts, and perirolandic white matter.

Newborn Screening (NBS) Results:
The NBS revealed markedly elevated levels of branched-chain amino acids, consistent with maple syrup urine disease (MSUD).

Differential Diagnosis:

  • Nonketotic hyperglycinemia (NKH)

  • Maple syrup urine disease (MSUD)

  • Canavan disease

  • Hypoxic ischemic encephalopathy (HIE)

Final Diagnosis:
Maple Syrup Urine Disease (MSUD)

Discussion

Maple Syrup Urine Disease (MSUD):
Also known as branched-chain ketoacid dehydrogenase deficiency, MSUD is a rare autosomal recessive disorder that affects the metabolism of the branched-chain amino acids (BCAAs): leucine, isoleucine, and valine. The disease is named for the characteristic sweet odor in the urine, serum, and sweat of affected individuals.

Epidemiology:
The global incidence of MSUD is approximately 1 in 180,000 to 185,000 live births. However, the condition is more prevalent in certain populations, such as Ashkenazi Jews and Old Order Mennonite communities in the United States, where consanguineous marriages are more common.

Pathophysiology:
A deficiency in the quantity or function of branched-chain ketoacid dehydrogenase (BCKD) leads to the accumulation of BCAAs and their corresponding branched-chain ketoacids in the plasma, urine, and cerebrospinal fluid. These accumulated metabolites inhibit pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, disrupting the citric acid cycle. This interference impairs amino acid synthesis and leads to cerebral edema and abnormal myelination.

Clinical Presentation:
MSUD has two main clinical forms: the classic and the intermittent type. The classic form typically manifests within the first week of life, whereas the intermittent type may present later, between 5 months and 2 years of age.
The timing of symptom onset correlates with the degree of BCKD deficiency. Most patients appear normal at birth but develop symptoms within the first few hours to days of life. Common symptoms include poor feeding, vomiting, hypoglycemia, hypotonia, seizures, and potentially death.

Imaging Findings:
Brain MRI is the imaging modality of choice for identifying the characteristic features of MSUD.
Symmetrical white matter edema is a hallmark of the disease, typically seen as diffuse low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Similarly, DWI demonstrates restricted diffusion not only in the brainstem white matter but also in the basal ganglia, thalami, internal capsules (often the posterior limbs), optic radiations, and perirolandic white matter.

However, due to the intrinsic hypomyelination of the neonatal brain, findings on T1W and T2W images may be inconspicuous. Thus, DWI is the most sensitive sequence for revealing the classic imaging features of MSUD.

Differentiating MSUD from similar disorders such as NKH, Canavan disease, and HIE based solely on MRI can be challenging.

  • NKH may show similar diffusion restriction in the posterior limbs of the internal capsule, brainstem, and cerebellum. However, NKH typically presents with elevated serum glycine, and blood glucose levels are high (compared to normal or low in MSUD). Intractable seizures are also more common in NKH than in MSUD.

  • HIE can mimic MSUD on imaging but is usually associated with a history of birth complications, such as prolonged labor, meconium aspiration, or low APGAR scores. In this case, no such perinatal issues were noted, and symptoms began 48 hours post-delivery, whereas HIE tends to present immediately after birth. However, severe MSUD may also present as early as 24 hours postnatally.

  • Canavan disease also has overlapping imaging features with MSUD, but is often associated with megalencephaly. Unlike MSUD, Canavan disease tends to spare the basal ganglia and internal capsule and primarily affects subcortical U-fibers.

Newborn Screening (NBS):
In regions where NBS is available, the test is typically performed within the first 10 days of life (often around day 5). It is used to screen for various inherited or congenital metabolic disorders, including sickle cell anemia, cystic fibrosis, congenital hypothyroidism, phenylketonuria (PKU), MSUD, isovaleric acidemia (IVA), glutaric aciduria type 1, homocystinuria (HCU), and medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

Early detection is crucial, as many of these conditions can lead to fatal or irreversible consequences if untreated. Prompt diagnosis allows for early intervention, which can significantly improve outcomes. In the case of MSUD, early dietary management is highly effective in reducing disease morbidity.

Treatment:
Current treatment options for MSUD include dietary management and liver transplantation.
Dietary therapy involves restricting natural protein intake and using medical formulas that are free of BCAAs.

Key Points:

  • Brain MRI may serve as the initial clue for diagnosing MSUD, especially in settings where newborn screening is not readily available.

  • The DWI sequence is critical for detecting the characteristic imaging features of MSUD.

  • T1W and T2W sequences may be less specific in neonates due to inherent hypomyelination.

Reference

(1)      Cheng A, Han L, Feng Y, et al. MRI and clinical features of maple syrup urine disease: Preliminary results in 10 cases. Diagn Interv Radiol. 2017 Sep-Oct;23(5):398-402. doi: 10.5152/dir.2017.16466. PMID: 28830848; PMCID: PMC5602367.

(2)      Allahwala A, Ahmed S, Afroze B. Maple syrup urine disease: Magnetic resonance imaging findings in three patients. J Pak Med Assoc. 2021 Apr;71(4):1309-1313. doi: 10.47391/JPMA.1341. PMID: 34125801.

(3)      Mohamed MM, Bakheet MA, Magdy RM, El-Abd HS, Alam-Eldeen MH, Abo-Haded HM. The clinico-radiological findings of MSUD in a group of Egyptian children: Contribution to early diagnosis and outcome. Mol Genet Genomic Med. 2021 Oct;9(10):e1790. doi: 10.1002/mgg3.1790. Epub 2021 Aug 25. PMID: 34432377; PMCID: PMC8580081.

(4)      Li Y, Liu X, Duan CF, Song XF, Zhuang XH. Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease: Report of three cases. World J Clin Cases. 2021 Mar 16;9(8):1844-1852. doi: 10.12998/wjcc.v9.i8.1844. PMID: 33748233; PMCID: PMC7953394.






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