Alpers–Huttenlocher syndrome: the role of a multidisciplinary health care team

Figures & data

Table 1 Major POLG clinical syndromes

Age of onset	Syndrome
Neonatal/infancy	Myocerebrohepatopathy spectrum (MCHS)^Citation17,Citation18
Infancy/childhood/juvenile	Alpers–Huttenlocher syndrome (AHS)^Citation10,Citation19^–^Citation21
Adolescent	Myoclonus, epilepsy, myopathy, sensory ataxia (MEMSA)^Citation23
Adolescent/young adult	Ataxia neuropathy spectrum (ANS)^Citation24
Adult/elderly
Adult	Sensory ataxia, neuropathy with dysarthria, and ophthalmoplegia (SANDO)^Citation25,Citation26
Adult	Autosomal-recessive progressive external ophthalmoparesis (arPEO)^Citation15
Adult	Autosomal-dominant progressive external ophthalmoparesis (adPEO)^Citation15

Figure 1 Functional and structural domains of the polymerase-γ protein.

Notes: The N-terminal domain (TD) comprises the targeting sequence for the protein to be transported into the mitochondrion. There are two thumb regions (T) that separate the endonuclease and polymerase regions from the linker region. The exonuclease domain has three essential motifs (I, II, III) needed for full activity. The polymerase region contains one thumb region (T) and the palm (two motifs) and finger, which contain regions A, B, and C. These motifs are needed for complete and optimal functioning of the protein. The arrows point to the amino acid that begins the subdomains.
Abbreviations: AID, accessory-interacting determinant; IP, intrinsic processivity.

Table 2 Diagnostic criteria for the clinical diagnosis of Alpers–Huttenlocher syndrome

1. Clinical triad of medically refractory seizures, psychomotor regression, and hepatopathy. However, in the absence of hepatopathy or additional findings:

a. Diagnosis can only be confirmed either by POLG sequencing, liver biopsy, or postmortem examination

2. Additional clinical findings (at least two findings must be present from):

a. cerebral volume loss (central more than cortical with ventriculomegaly) on repeated magnetic resonance imaging or computed tomography

b. cranial proton magnetic resonance spectroscopy indicating reduced N-acetyl aspartate, normal creatine, and elevated lactate

c. elevated cerebrospinal fluid protein (>100 mg/dL)

d. at least one electroencephalogram revealing multifocal paroxysmal activity with high-amplitude δ-slowing (200–1,000 μV) and spikes/polyspikes (10–100 μV, 12–25 Hz)

e. cortical blindness or optic atrophy

f. abnormal visually evoked potentials and normal electroretinogram findings

g. isolated complex IV or a combination of complex I, III, and IV electron-transport chain defects (≤20% of normal) upon liver respiratory chain testing

h. quantitative mitochondrial DNA depletion in skeletal muscle or liver (35% of mean)

i. elevated blood or cerebrospinal lactate (3 mM) on at least one occasion in the absence of acute liver failure

j. deficiency in polymerase-γ enzymatic activity (≤10%) in skeletal muscle or liver

k. a sibling confirmed as manifesting Alpers–Huttenlocher syndrome.

Table 3 Clinical features encountered in Alpers–Huttenlocher syndrome

Central nervous system

Seizures

Headache

Vision Loss

Movement disorders (myoclonus, dystonia, tremor, chorea)

Ataxia: sensory neuropathy

Ophthalmoplegia

Ptosis

Cognitive impairment

Psychiatric symptoms (anxiety, depression)

Respiratory

Obstructive and central apnea

Gastrointestinal

Gastronintestinal dysmotility

Dysphagia

Liver failure

Nutritional failure

Musculoskeletal

Muscle weakness

Cardiac

Cardiomyopathy

Arrhythmia

Table 4 Specific histological features of Alpers–Huttenlocher syndrome

At least three of the features of hepatopathy necessary for diagnosis (Wilson disease excluded):

1. bile ductular proliferation

2. microvesicular steatosis

3. collapse of liver-cell plates

4. hepatocyte dropout of focal necrosis with or without portal inflammation

5. bridging fibrosis or cirrhosis

6. parenchymal disarray or disorganization of the normal lobular architecture

7. regenerative nodules

8. oncocytic change (mitochondrial proliferation associated with intensely eosinophilic cytoplasm) in scattered hepatocytes not affected by steatosis.

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