Diagnostic Approach to Neurotransmitter Disorders

Since many monoamine neurotransmitter disorders may present in similar fashion (often with normal imaging), it is useful to consider them as a group and interpret diagnostic findings in the context of the specific clinical features. Historically, some of these disorders in which there was detectable hyperphenylalaninemia were grouped under the header of “atypical phenylketonuria” to reflect the combination of elevated phenylalanine, a complex neurological phenotype, and the lack of improvement with a restricted diet. The availability of cerebrospinal fluid (CSF) neurotransmitter and pterin levels greatly aided the specification of these disorders, as many carry a specific CSF profile. Unfortunately, CSF neurotransmitter testing is not widely available and requires specialized processing for accurate interpretation. Subsequently, several genes have been identified in association with these diseases, and currently many patients are diagnosed by virtue of clinical presentation, response to levodopa, CSF analysis. and/or gene panels (Table 9.1).

Blood tests that may assist the clinician include phenylalanine (PA) and prolactin levels. In some diseases (e.g. due to GCH1 or SPR mutations), the baseline PA level may be normal but an oral loading test will demonstrate an abnormally high PA:tyrosine ratio, indicating subclinical deficits in PA hydroxylation in the liver. This test may be useful when lumbar puncture and CSF analysis are not available, but false positives and false negatives have been reported [19]. Urine testing includes measurement of pterins and neurotransmitter metabolites. This may be particularly useful in aromatic L-amino acid decarboxylase (AADC) deficiency (increased 3-OMD and VLA with decreased VMA) and brain dopamine–serotonin transporter deficiency (elevations of urinary 5-HIAA and HVA with decreased neopterin and dopamine). CSF neurotransmitter analysis probably provides the most information, but unfortunately this may not be available in several parts of the world. Gene testing and/or functional assays (e.g. fibroblast enzyme assays) can help confirm the suspected diagnoses [20, 21].

Autosomal-Dominant GTP Cyclohydrolase 1 Deficiency (Segawa Disease)

Segawa disease, also known as DYT5a, is the prototype of dopa-responsive dystonia. The disorder results from mutations in the GCH1 gene, responsible for the enzyme GTPCH1. The enzyme is involved in the first step in the synthesis of tetrahydrobiopterin (BH4), an important cofactor in the dopamine and serotonin synthetic pathway (Figure 9.1). The classic presentation occurs in childhood (mean age 6 years), starting with foot dystonia that is usually much worse at the end of the day. The disorder affects females more than males with a 2.5:1 ratio. Symptoms gradually progress to other limbs in the ensuing years, and diurnal fluctuation becomes less obvious. Postural tremor may appear in the second decade. Adolescents and older patients may present with upper-extremity tremor, parkinsonism, and rigidity. There is wide phenotypic variation, and other features have been described, such as paroxysmal dystonia. Untreated patients have been misdiagnosed with cerebral palsy or hereditary spastic paraplegia [17, 22].

The diagnosis of Segawa disease relies on a levodopa trial, biochemical tests, and genetic confirmation. A levodopa trial shows marked and sustained improvement, leading some authors to suggest that every child with unexplained dystonia merits a levodopa challenge. Plasma PA levels are normal, but a PA oral loading test may be abnormal. Serum prolactin may be elevated. CSF neurotransmitters may reveal low levels of HVA, 5-HIAA, BH4, and neopterin, although HVA and 5-HIAA may be only slightly reduced or normal. Several mutations in GCH1 have been described; sequence analysis detects about 60% of patients. A portion of the remaining individuals with functional evidence of GTPCH1 deficiency may have deletions or duplications (potentially identified through multiplex-ligation-dependent probe amplification or chromosomal microarray); others may harbor mutations in non-coding regions or in yet-unidentified regulatory genes [17].

Treatment with levodopa leads to a striking response with sustained benefits. Patients with Segawa disease may demonstrate peak-dose dyskinesias (especially when the dose is being uptitrated, but later as well). Nevertheless, they do not develop motor fluctuations or wearing off, and dyskinesias improve with reduction in levodopa dosage [17].

Autosomal-Recessive GTP Cyclohydrolase 1 Deficiency

Autosomal-recessive GTPCH1 deficiency may exist in a continuum, with phenotypic differences between homozygotes and compound heterozygotes [23]. Homozygous mutations more frequently lead to severe symptoms, including developmental delay, hypotonia, autonomic dysfunction, seizures, and a wide variety of movement disorders including dystonia and parkinsonism. Hyperphenylalaninemia can be detected on newborn screening [17]. Patients with compound heterozygous variants in GCH1 may present with a phenotype labeled, “dystonia with motor delay,” without overt hyperphenylalaninemia [23]. Nevertheless, this phenotype is not exclusive and has also been reported in the context of homozygous mutations [24]. Some patients present with hypotonia, dystonia, and parkinsonism with onset in the first year of life (Video 9.1). CSF neurotransmitter metabolites are usually reduced (HVA, 5-HIAA, BH4, neopterin); serum prolactin may be elevated and urine pterins are reduced. Treatment should include levodopa, 5-HTP, and BH4 replacement [17].

6-Pyruvoyltetrahydropterin Synthase Deficiency

6-Pyruvoyltetrahydropterin synthase (PTPS) deficiency is caused by mutations in the PTS gene and appears to be most frequent in Asian populations. Clinical features may include neonatal onset with intrauterine growth restriction, microcephaly, hypokinetic–rigid syndrome, and developmental delay. Dystonia, chorea, and oculogyric crises may be present, as well as seizures. Hyperphenyalaninemia is usually detected through newborn screening. CSF levels of HVA, 5-HIAA, and BH4 are low, but neopterin can be elevated. Urine shows elevated total biopterin with decreased neopterin. Patients are treated with a similar regimen as autosomal-recessive GTPCH1 deficiency, but may require slightly higher doses; occasionally dopamine agonists and monoamine oxidase-B (MAO-B) inhibitors are necessary to avoid on–off phenomena [17].

Sepiapterin Reductase Deficiency

Sepiapterin reductase (SPR) deficiency is inherited in an autosomal-recessive manner, caused by mutations in the SPR gene, coding for the enzyme responsible for the final steps in BH4 synthesis. Symptoms are similar to other disorders with catecholamine and serotonin deficiency. In the largest series to date, limb dystonia, weakness, and oculogyric crises with diurnal fluctuation occurred in > 65% of patients. One or more parkinsonian features (tremor, bradykinesia, masked facies, and rigidity) were noted in 45–65% of patients [25]. Head and limb resting tremor (sometimes inhibited by touch or spontaneous movement) was reported. Diurnal fluctuation may be absent and some patients have been misdiagnosed with cerebral palsy. Other features, such as seizures, sleep disturbances, and cognitive disability, may be present [17, 25].

Plasma PA and urine pterins are normal, but the oral PA loading test is usually abnormal. CSF levels of HVA and 5-HIAA are low, with elevations in total biopterin, BH2, and sepiapterin levels. Treatment with levodopa often leads to improvement, but patients may be sensitive to early dyskinesias. Starting with a low dose, followed by slow titration, is advised. Adding 5-HTP may lead to additional benefits in motor and sleep symptoms beyond that achieved with levodopa. Additional carbidopa may be necessary to minimize 5-HTP related gastrointestinal distress [17, 25].

Dihydropteridine Reductase Deficiency

The dihydropteridine reductase (DHPR) enzyme is involved in BH4 regeneration as well as maintenance of cerebral folate. The disease is best detected on newborn screening, showing hyperphenylalaninemia. Newborns may be initially asymptomatic but, untreated, the disease may lead to developmental delay, bulbar dysfunction, axial hypotonia with limb dystonia, tremor, choreoathetosis, and seizures. Microcephaly, cerebral atrophy, and intracranial calcifications may be present [26]. Parkinsonism has been described in patients with longstanding disease [27]. CSF has low levels of HVA, 5-HIAA, and 5-MTHF, and high levels of BH2 and high or normal levels of biopterin. Treatment involves levodopa, 5-HTP, and folinic acid; occasionally a PA-restricted diet is required [17, 26].

Tyrosine Hydroxylase Deficiency (also known as DYT5b or DYT-TH)

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine synthesis. Autosomal-recessive mutations in the TH gene can lead to two clinical phenotypes, although overlap exists: type A (69% of patients) have a dystonic and/or hypokinetic–rigid syndrome, also called “infantile parkinsonism,” with onset in the first years of life [28]. Type B patients (31%) have early onset (0–3months) of a complex encephalopathy, including severe parkinsonism, autonomic dysfunction, oculogyric crises, and seizures [17, 28, 29].

In type A TH deficiency, the age at onset ranges from 2 months to 5 years. Symptoms may start in one limb and generalize. In the early phases of the disease, the severity of dystonia may fluctuate, either diurnally (worse in the afternoon) or in apparent episodic fashion within days. This latter aspect may mimic paroxysmal dystonia. Tremor, chorea, oculogyric crises, and autonomic and behavioral symptoms are either mild or absent. In some patients, parkinsonism may dominate the picture early with the later development of dystonia. Treatment with levodopa leads to improvement, some patients attaining the ability to walk and show normal cognitive skills [28].

Type B disease is often accompanied by perinatal complications (fetal distress, asphyxia), initially leading to a suspicion for epileptic encephalopathies or mitochondrial disease. There is usually marked hypokinesia and bradykinesia, hypotonia mixed with superimposed limb dystonia, or spells of generalized dystonia. The episodic worsening can have autonomic dysfunction with diaphoresis, drooling, and fever of unknown origin. EEG may indicate seizures, but not all clinical spells are epileptic. Movements are jerky, sometimes with tremors or myoclonus. Bilateral ptosis and oculogyric crises are seen. Treatment with levodopa is less consistently effective, and may take weeks to be noticeable. Patients with type B can be extremely sensitive to levodopa, developing dyskinesias at very low doses. Despite improvement in motor symptoms and development, many patients with type B TH deficiency are left with intellectual disability [28].

CSF testing demonstrates low HVA and normal levels of 5-HIAA (HVA:5-HIAA ratio < 1). Given the sensitivity that patients with TH may have to dyskinesias, some authors recommend starting levodopa at low doses (0.5–1 mg/kg per day, divided over four to six doses per day), increased gradually by 0.1–0.5 mg/kg per day every month. Dyskinesias may respond to lowering the levodopa dosage (sometimes with adjunct treatment using MAO-B inhibitors or anticholinergics) or using amantadine [28, 30].

Aromatic L-Aminoacid Decarboxylase Deficiency

This autosomal-recessive condition is caused by mutations in the DDC gene, which encodes for the AADC enzyme: the final step in dopamine and serotonin synthesis. AADC deficiency leads to a severe disease with combined deficiency of these neurotransmitters. In most patients, symptoms are evident before 18 months of life, with hypotonia (95%) and oculogyric crises (86%). Developmental delay with cognitive disability is common. Autonomic dysfunction is seen with several features (ptosis, diaphoresis, temperature dysregulation, nasal congestion, fasting hypoglycemia, and impaired stress response). The movement disorder phenotype is complex, and can be seen in about 50% of patients. This includes hypokinesia (32%), dystonia (53%), athetosis (27%), and chorea (22%) [17, 21].

Neuroimaging can be abnormal, with global atrophy, hypomyelination, a thin corpus callosum, or non-specific white matter abnormalities. EEG may be slow or with polyspike activity. CSF testing demonstrates low levels of HVA, 5-HIAA, and MHPG. There is elevation of 5-HTP and 3-OMD. Urine levels of catecholamine metabolites can be helpful in AADC deficiency, with elevations of 3-OMD and VLA [17, 21].

Treatment of AADC deficiency involves using dopamine agonists and MAO-B inhibitors with supplementation of pyridoxine (or PLP) and folinic acid. Usually the two latter agents are started first, as pyridoxine (after conversion to PLP) can boost residual AADC activity and folinic acid prevents cerebral folate deficiency. Dopamine agonists such as bromocriptine, pramipexole, and ropinirole are beneficial; rotigotine may have an advantage given its wide D1–D5 receptor activity and additional serotoninergic and noradrenergic effects [17]. Levodopa is not first-line therapy, and if used the commercially available forms with decarboxylase inhibitors should be avoided.

Preliminary, open-label phase 1/2 data have shown promising results for gene therapy for AADC deficiency. The human AADC gene was injected in the bilateral putamina through stereotactic surgery using an adeno-associated virus (AAV) vector [31]. Further research is underway (ClinicalTrials.gov NCT02852213).

Brain Dopamine–Serotonin Vesicular Transport Disease (SLC18A2)

Mutations in the SLC18A2 gene, encoding for the vesicular transport protein VMAT2, causes this autosomal-recessive transportopathy with deficiencies in dopamine, norepinephrine, and serotonin. This rare disorder has been described in two different kindreds only. The VMAT2 protein facilitates neurotransmitter loading into synaptic vesicles. Clinical features included an early-onset disorder with axial hypotonia, superimposed limb dystonia, developmental delay, and oculogyric crises. As with other neurotransmitter disorders, autonomic dysfunction and sleep disturbances are observed. Parkinsonism, manifested by hypomimia, hypokinesia, and shuffling gait were observed in adolescent patients. Neuroimaging and CSF analysis are non-diagnostic, but a specific pattern on urine testing was seen with high levels of HVA and 5-HIAA and low dopamine and epinephrine. Treatment with levodopa may lead to clinical worsening, but dopamine agonists caused motor improvement [20, 32].

Dopamine Transporter Deficiency Syndrome (SLC6A3)

This autosomal-recessive condition is caused by mutations in the SLC6A3 gene encoding for a dopamine transporter. This protein is located at the presynaptic membrane and is responsible for the uptake of dopamine from the synaptic cleft. Typical cases present in the first year of life with developmental delay, axial hypotonia, and hyperkinetic movements (dystonia and dyskinesias), occasionally misdiagnosed as dyskinetic cerebral palsy. With time, hypomimia, rigidity, and bradykinesia may ensue. Atypical cases with presentation in the second decade of life with tremor, focal dystonia, and bradykinesia have been described. Oculogyric crises and ocular flutter are seen. CSF analysis demonstrates an elevation in the dopamine metabolite HVA, with associated elevation in the HVA:5-HIAA ratio. Neuroimaging is structurally normal, but functional imaging with ¹²³I (DaTscan ©) demonstrates a loss of dopamine transporter activity in the basal ganglia. Levodopa and dopamine agonists may provide modest benefit.

Copper

Wilson disease is an autosomal-recessive disorder in the ATP7B gene leading to copper overload in several tissues. The disease has protean manifestations, including hepatic, neurologic, and psychiatric symptoms. In general, children are more likely to have disease-onset with liver failure (age ranging from 9 years to 13 years); teenagers and young adults can present with psychiatric and neurological symptoms (age ranging from 15 years to 21 years) [33]. Systemic features may range from asymptomatic elevation in liver function or visceromegaly to hemolytic anemia, frank liver failure, and cirrhosis. The most common neurological symptoms include dysarthria, gait abnormalities, tremor, dystonia, and parkinsonism [34, 35]. Practically every movement disorder has been described in Wilson disease (e.g., chorea, ataxia, myoclonus), as well as atypical features such as seizures, pyramidal signs, neuropathy, autonomic dysfunction, and others. Neurological features are so broad that authors have tried to classify patients by predominant phenotype; one such division separates into four groups: dystonia, tremor, rigidity–tremor, or rigidity [34]. The distinction is challenging since frequently there will be mixed symptoms. Psychiatric symptoms are equally diverse and often precede neurological manifestations [35].

Parkinsonism may occur in 30–66% of patients with Wilson disease. When present, it is more often in association with other neurological features – uncommonly, it may be an isolated, presenting manifestation. Patients present with rigidity, bradykinesia with micrographia, hypomimia, and postural instability. Resting tremor can occur, but is uncommon. Treatment with levodopa is usually ineffective or leads to a modest improvement [34, 35].

A characteristic neurological feature of Wilson disease is an exaggerated, unnatural smile caused by dystonic retraction of the upper lip and orofacial musculature, termed “risus sardonicus.” The vast majority of patients with neurological manifestations (100% in some series) will have copper deposition in Descemet’s membrane of the cornea, leading to a brownish discoloration at the limbus, termed a Kayser–Fleischer ring [34, 35]. Clinicians should suspect Wilson disease in any patient with an unexplained movement disorder and/or liver disease, especially if some of these characteristic features are present.

Important tests in Wilson disease (besides liver function and tests for hemolytic anemia) include serum ceruloplasmin and 24-hour urine copper excretion. Slit-lamp examination is necessary to evaluate for Kayser–Fleischer rings. Molecular testing can be helpful. If suspicion is high, a liver biopsy can demonstrate hepatic copper deposition. MRI is often abnormal in patients with neurological symptoms and demonstrates T2 hyperintense signals in the basal ganglia, thalamus, midbrain, and pons. The disorder is treatable with chelating agents to prevent copper overload.

Iron

Iron accumulation in the brain occurs in a group of disorders named neurodegeneration with brain iron accumulation (NBIA) disorders. This group encompasses several diseases with the shared feature of high levels of iron in the basal ganglia. There is some variation in the clinical presentation and etiology, but presumably similar pathophysiology based on degenerative changes in the substantia nigra and globus pallidus [36]. The diagnosis is most commonly considered when signal changes are found in iron-sensitive sequences in MRI (susceptibility-weighted imaging [SWI], T2* and R2* mapping) in a patient with a movement disorder, or when a pathogenic mutation is found in one of genes associated with NBIA disorders. The current classification system organizes disorders by their genetic basis, recognizing allelic heterogeneity within each disease. The most common NBIA disorder is pantothenate kinase-associated neurodegeneration (PKAN; associated with mutations in the PANK2 gene). Together with PKAN, three other genes (PLA2G6, C19orf12, WDR45) comprise 85% of all NBIA disorders [36].

Pantothenate-Kinase Associated Neurodegeneration

PKAN accounts for half of cases of NBIA disorders. Due to population allele frequency, the prevalence in certain geographic areas (e.g. Dominican Republic) may be higher. The disorder spans a continuum of phenotypical presentations: on one end, patients present with developmental delay and focal limb dystonia in the first decade (mean age 3 years). Dystonia frequently involves the lower extremities, leading to falls and gait changes. Dystonia tends to generalize with time and there may be superimposed spasticity. Pigmentary retinopathy and acanthocytes on a peripheral blood smear can be detected in some patients. On the other end of the spectrum (so-called atypical cases), there is a later age of onset, with parkinsonism, neuropsychiatric symptoms, and dystonia. Patients with onset in the second decade of life often have mixed dystonia and parkinsonism, and are more likely to have parkinsonism dominating the motor phenotype [36]. MRI reveals a pathognomonic signature on T2-weighted sequences consisting of central hyperintensity of the globus pallidus with a halo of hypointense signal (“eye of the tiger” sign; Figure 9.2).

Figure 9.2 MRI of a patient with PKAN. Axial T2-weighted imaging of the globus pallidus demonstrating a central pallidal hyperintense signal surrounded by hypointense signal (“eye of the tiger”).

Related posts:

Chapter 1 – Treatable Metabolic Movement Disorders: The Top 10 Chapter 10 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Spasticity Chapter 7 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Ataxia Chapter 13 – Disorders of Energy Metabolism: GLUT1 Deficiency Syndrome and Movement Disorders Chapter 21 – Neurotransmitter Disorders: Disorders of Dopamine Metabolism and Movement Disorders Chapter 27 – Purine Metabolism Defects: The Movement Disorder of Lesch–Nyhan Disease

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