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Biogenic amines neurotransmitter disorders

Neurotransmitters include the catecholamines (dopamine, norepinephrine, and epinephrine) and the indoleamines (serotonin and melatonin). They are chemical messengers, which mediate, amplify, or modulate synaptic Transmission between neurons in the brain. Consequently, neurotransmitters are involved in central brain functions including the control of movements and behavior, neuronal excitation and inhibition, the regulation of body temperature, pain threshold, memory, and a host of other processes. Inherited deficiencies of neurotransmitters encompass defects of neurotransmitter biosynthesis and catabolism, as well as defects of neurotransmitter transporters. They result in a wide variety of clinical signs and symptoms. This chapter will focus on primary disorders of serotonin and dopamine metabolism. Described defects are deficiencies of tyrosine hydroxylase (TH), aromatic l -amino acid decarboxylase (AADC), dopamine ß -hydroxylase (D ß H), monoamine oxidase A, as well as the hereditary dopamine transporter syndrome and the brain dopamine-serotonin vesicular transport (VMAT2) disease.

Neurotransmitter disorders are important to recognize because early diagnosis and prompt therapeutic intervention seem to improve motor and cognitive outcome. The disease predominantly starts during infancy and early childhood. The specific clinical presentation of individual neurotransmitter diseases is determined by the type and severity of the underlying disorder. The clinical phenotype is not characteristic but can mimic that of other neurological disorders. Although a detailed clinical history and physical examination are essential, the diagnosis is almost exclusively based on the quantitative determination of neurotransmitters or their metabolites in cerebrospinal fluid (CSF). The additional determination of pterin metabolites is needed for the differentiation from deficiencies of BH 4 metabolism. Every diagnosis must be confirmed by molecular testing. The aim of treatment is to restore neurotransmitter homeostasis. Bypassing the metabolic block using levodopa/carbidopa together with dopamine agonists has led to remarkable clinical improvement in TH deficiency. In patients with AADC deficiency and with dopamine receptor deficiency, syndrome treatment options are limited and in many cases not satisfactory. Patients with DβH deficiency benefit from dihydroxyphenylserine (DOPS) administration. While patients with VMAT2 defects benefit from treatment with a dopamine receptor agonist, no specific treatment with sustained effect for MAO-A deficiency or dopamine transporter deficiency has been described.

For AADC deficiency consensus care guidelines developed by iNTD network members can be downloaded here: http://rdcu.be/E00D

This text is an extract from “Physician´s Guide to the Diagnosis, Treatment and Follow-Up of Inherited Metabolic Diseases”, Editors: Nenad Blau, Marinus Duran, K. Michael Gibson, Carlos Dionisi-Vici, Publisher: Springer

References:

Opladen T, Hoffmann GF, Neurotransmitter Disorders, Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, N. Blau et al. (eds.)

Disorders of Phenylalanine and Tetrahydrobiopterin (BH4) Metabolism

Hyperphenylalaninemia (HPA), a disorder of phenylalanine catabolism, is caused primarily by a deficiency of the hepatic phenylalanine-4-hydroxylase (PAH) or by one of the enzymes involved in its cofactor tetrahydrobiopterin (BH4) biosynthesis (GTP cyclohydrolase I (GTPCH) and 6- pyruvoyl-tetrahydropterin synthase (PTPS)) or regeneration (dihydropteridine reductase (DHPR) and pterin- 4acarbinolamine dehydratase (PCD)) (Blau et al. 2001). BH4 is known to be the natural cofactor for PAH, tyrosine-3- hydroxylase, and tryptophan-5-hydroxylase as well as all three isoforms of nitric oxide synthase (NOS) (Werner et al. 2011), the latter two being the key enzymes in the biosynthesis of the neurotransmitters dopamine and serotonin. Thus, with two exceptions (see below) any cofactor defect will result in a deficiency of biogenic amines accompanied by HPA. Because phenylalanine is a competitive inhibitor of the uptake of tyrosine and tryptophan across the blood-brain barrier and of the hydroxylases of tyrosine and tryptophan, depletion of catecholamines and serotonin occurs in untreated patients with PAH deficiency. Both groups of HPA (PAH and BH4 deficiency) are heterogeneous disorders varying from severe, e.g., classical phenylketonuria (PKU), to mild and benign forms Because of the different clinical and biochemical severities in this group of diseases, the terms “severe” or “mild” will be used based upon the type of treatment and involvement of the CNS. For the BH4 defects, symptoms may manifest during the first weeks of life but usually are noted within the first half year of life. Birth is generally uneventful, except for an increased incidence of prematurity and lower birth weights in severe PTPS deficiency (Opladen et al. 2012).

Two disorders of BH4 metabolism may present without HPA. These are dopa-responsive dystonia (DRD; Segawa disease) (Segawa 2011) and sepiapterin reductase (SR) deficiency (Friedman et al. 2012). While DRD is caused by mutations in the GTPCH gene and is inherited in an autosomal dominant manner, SR deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amine deficiencies. DRD usually presents with a dystonic gait and diurnal variation, while many patients with SR deficiency have an initial diagnosis of cerebral palsy. At least two reports describe heteroallelic patients with DRD suggesting a wide spectrum of GTPCH variants.

A diagnosis of HPA is usually based upon the confirmation of an elevated blood phenylalanine level obtained on a normal diet, following a positive newborn screening test. Normal breast milk or formula feeding for only 24 h is sufficient to raise the baby’s blood phenylalanine sufficiently to trigger a positive test level (>120 μmol/l). In general, an infant will be found to have a positive screening test 12 h postnatal. The tandem mass spectrometry (TMS) is today the method of choice for newborns screening. A detection as early as possible is essential in order to introduce appropriate treatment to prevent effects on mental development.

In PAH and BH4 deficiencies, factors like a relatively high phenylalanine intake or catabolic situations may be responsible for high phenylalanine concentrations in blood. Once HPA has been detected, a sequence of quantitative tests enables the differentiation between variants, i.e., BH4-non-responsive PKU (usually the patients with the most severe PAH deficiency), BH4-responsive PKU (Heintz et al. 2013), and BH4 deficiencies. Because the BH4 deficiencies are actually a group of diseases which may be detected because of HPA, but not simply and routinely identified by neonatal mass screening, selective screening for a BH4 deficiency is essential in every newborn with even slightly elevated phenylalanine levels. Differential testing for BH4 deficiencies should be done in all newborns with plasma phenylalanine levels greater than 120 μmol/l (2 mg/dl), as well as in older infants and children with neurological signs and symptoms.

BH4 deficiencies presenting without HPA are detectable only by investigations for neurotransmitter metabolites and pterins in CSF or by clinical signs and symptoms. In DRD, a phenylalanine loading test, a trial with l -dopa, and enzyme activity measurement in cytokine-stimulated fibroblasts and molecular testing are confirmatory for the diagnosis. SR deficiency can be definitely diagnosed by an enzyme assay of cultured fibroblasts or DNA testing, but phenylalanine loading test is also positive.

The goals of treatment are to control HPA in PAH and BH4 deficiencies and to restore CNS neurotransmitter homeostasis in BH4 deficiencies (Blau et al. 2010). To that aim, dietary restriction in phenylalanine intake, supplementation with BH4, and oral administration of dopamine and serotonin precursors (l-dopa/carbidopa and 5- hydroxytryptophan, respectively), as well as some other drugs are available (Opladen et al. 2012). In this respect, it should be taken into account that some patients with PAH deficiency, historically only treated by diet, can be treated with BH4 (sapropterin dihydrochloride). At the same time, in patients with DPHR deficiency, in whom historically the HPA was not treated with BH4, the diet restricting phenylalanine intake is the treatment of choice. Only about 20 % of DHPR-deficient patients are on BH4 treatment (Opladen et al. 2012).

Late detection of PAH or BH4 deficiencies and late introduction of treatment lead to irreversible brain damage. In contrast to early and continuously treated patients with PAH deficiency, some patients with BH4 deficiencies show progressive neurological deterioration despite treatment. Patients with PCD deficiency are at risk of developing early-onset diabetes in puberty.

References:

Blau N, Thöny B, Cotton RGH, Hyland K (2001) Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet al, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1725–1776
Werner ER, Blau N, Thöny B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438:397–414
Opladen T, Hoffmann FG, Blau N (2012) An international survey of patients with tetrahydrobiopterin defi ciencies presenting with hyperphenylalaninaemia. J Inerit Metab Dis 35:963–73
Segawa M (2011) Hereditary progressive dystonia with marked diurnal fl uctuation. Brain Dev 33:195–201
Friedman J, Roze E, Abdenur JE et al (2012) Sepiapterin reductase defi ciency: a treatable mimic of cerebral palsy. Ann Neurol 71:520–530
Heintz C, Cotton RG, Blau N (2013) Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 34:927–936
Blau N, Van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427

Disorders of Folate Metabolism and Transport

Folates play an essential role in one-carbon methyl transfer reactions, mediating several biological processes including DNA synthesis, regulation of gene expression through methylation reactions, embryonic central nervous system development, synthesis and breakdown of amino acids, and synthesis of thymidines, purines, and neurotransmitters (Blount et al. 1997; Linhart et al. 2009; Ghoshal et al. 2006 ; Pogribny et al. 2008 ; Fournier et al. 2002). In mammals, folates are mostly derived from exogenous sources as folate is stored in the liver for few months. The biologically active folic acid derivative is 5,6,7,8-tetrahydrofolate (THF). Dietary folate is absorbed in the intestine. In the cytoplasm, interconversion of 5,10-methylene-THF and 5,10-methenyl- THF, interconversion of 5,10-methenyl-THF and 10-formyl- THF, and the reaction of THF with formate to synthesize 10-formyl- THF are mediated by the MTHFD1 gene that encodes a trifunctional protein. Metabolism of 5,10- methylene-THF to 5-methyl-THF in the liver is catalyzed by methylene- THF reductase (MTHFR). 5-methyl-THF is then widely distributed in the bloodstream. The transport of 5-methyl-THF inside the cells is mediated by different transport systems that include the proton-coupled folate transporter (PCFT), the reduced folate carrier 1 (RFC1), and the two GPI-anchored receptors, folate receptor alpha (FRα) and beta (FRβ) (Matherly and Goldman 2003). The physiological form of folate, 5-methyl-THF is actively transported to the central nervous system by FRα- mediated endocytosis in choroid epithelial cells, reaching a higher concentration in the cerebrospinal fluid when compared to the serum. FRα is a high-affinity low-capacity receptor that functions at a nanomolar range of extracellular folate concentrations (Weitman et al. 1992). Thus far, seven different inherited disorders of folate metabolism are known which lead to folate deficiency including hereditary folate malabsorption, folate receptor alpha deficiency, methylenetetrahydrofolate reductase deficiency, methenyltetrahydrofolate synthetase deficiency, dihydrofolate reductase deficiency, and methylenetetrahydrofolate dehydrogenase deficiency (Watkins and Rosenblatt 2012 ; Watkins et al. 2011). Furthermore, in some cases, an additional disorder, namely, cerebral folate deficiency (CFD) caused by FOLR1 autoantibodies have also been described (Ramaekers and Blau 2004).

References:

Matherly LH, Goldman DI (2003) Membrane transport of folates. Vitam Horm 66:403–456
Weitman SD, Weinberg AG, Coney LR, Zurawski VR, Jennings DS, Kamen BA (1992) Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Res 52:6708–6711
Watkins D, Rosenblatt DS (2012) Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 35(4):665–670
Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, Majewski J, Rosenblatt DS (2011) Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband. J Med Genet 48:590–592
Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46:843–851
Fournier I, Ploye F, Cottet-Emard JM, Brun J, Claustrat B (2002) Folate defi ciency alters melatonin secretion in rats. J Nutr 132:2781–2784
Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94:3290–3295
Linhart HG, Troen A, Bell GW, Cantu E, Chao WH, Moran E, Steine E, He T, Jaenisch R (2009) Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations. Gastroenterology 136(227–235):e223
Ghoshal K, Li X, Datta J, Bai S, Pogribny I, Pogribny M, Huang Y, Young D, Jacob ST (2006) A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J Nutr 136:1522–1527
Pogribny IP, Karpf AR, James SR, Melnyk S, Han T, Tryndyak VP (2008) Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-defi cient diet. Brain Res 1237:25–34

Glycine Disorders

Nonketotic hyperglycinemia (glycine encephalopathy). The primary disorder of glycine is a deficiency of the main catabolic enzyme, the glycine cleavage enzyme. Glycine is part of many biochemical pathways, but a deficiency of the glycine cleavage enzyme removes the main catabolic breakdown of glycine resulting in increased levels of glycine. The disorder is known as nonketotic hyperglycinemia (NKH) or glycine encephalopathy. All forms of the disorder are characterized by cerebral dysfunction.

The glycine cleavage enzyme breaks glycine down into carbon dioxide and ammonia, and a methyl group is transferred to tetrahydrofolate creating methylenetetrahydrofolate. The enzyme consists of four subunits: the P-protein (pyridoxalcontaining subunit), the H-protein (hydrogen carrier protein), the T-protein (tetrahydrofolate- requiring protein), and the l -protein (lipoamide dehydrogenase protein). The P-protein requires pyridoxal-phosphate, and disorders that affect the availability of pyridoxal- phosphate (such as PNPO ) result in a secondary deficiency of the enzyme activity. The H-protein is lipoylated and disorders in the biogenesis of the lipoylation result in variant forms of nonketotic hyperglycinemia.

Patients with NKH most often present neonatally in the first week of life (Hennermann et al. 2012 ). They develop lethargy, fail to feed, and progress to coma with frequent hiccupping and seizures. They have severe hypotonia. They often have a burst suppression pattern on EEG. These patients spontaneously recover from respiratory failure and regain spontaneous breathing within the first 3 weeks of life. Patients presenting during infancy have hypotonia, lethargy, and seizures (spasms or myoclonic seizures) with either multifocal epilepsy or hypsarrhythmia on EEG.

References:

Dinopoulos A, Matsubara Y, Kure S (2005) Atypical variants of nonketotic hyperglycinemia. Mol Genet Metab 86:61–69
Hennermann JB, Berger JM, Grieben U et al (2012) Prediction of longterm outcome in glycine encephalopathy: a clinical survey. J Inherit Metab Dis 35:253–261

Serine Disorders

Serine is obtained from diet and is synthesized endogenously starting from the glycolytic intermediate 3- phosphoglycerate in three steps using the enzymes phosphoglycerate dehydrogenase (gene PHGDH), phosphoserine aminotransferase ( PSAT1 ), and phosphoserine phosphatase ( PSPH ). Three disorders of serine biosynthesis are known affecting each of the steps in this serine biosynthetic pathway (Tabatabaie et al. 2010). Characteristic for all three disorders is the decreased biosynthesis of serine resulting in serine deficiency. Serine is an essential component of phosphatidylserine, sphingolipids, and ceramides and is necessary for myelin development (de Koning et al. 2003). -Serine is converted through the racemase to d-serine, which is an NMDA receptor activator. Through the serine hydroxymethyltransferase enzyme, serine is converted into glycine and provides methylene- tetrahydrofolate which is important for thymidine synthesis.

3-Phosphoglycerate dehydrogenase deficiency (PHGDH) is an autosomal recessive condition and the most frequently reported cause of serine deficiency syndrome. In the severe infantile form, it presents in the neonatal period with congenital microcephaly, intractable seizures starting shortly after birth, and severe psychomotor retardation. A wide variation of seizure types are reported including West syndrome. The EEG patterns include hypsarrhythmia, multifocal epilepsy, and Lennox-Gastaut syndrome. They develop spastic tetraparesis, with adducted thumbs, and hyperexcitability. Variable symptoms observed in some patients include cataracts, hypogonadism, megaloblastic anemia, and nystagmus. The MRI of the brain shows a striking reduction in the volume of the white matter and very delayed to absent myelination. The cerebral white matter on T2 has a higher signal intensity than the cortex, indicative of a lack of myelin. There is also cortical and subcortical atrophy. MRS shows a decreased level of N -acetylaspartate/ creatine and increased choline /creatine in the white matter

Phosphoserine aminotransferase deficiency (PSAT1) was reported in a single family (Hart et al. 2007). They had acquired microcephaly, intractable seizures since early infancy, and hypertonia. Brain MRI showed generalized atrophy, a hypoplastic cerebellar vermis, and poor white matter development. Serine and glycine were deficient in plasma and CSF. Diagnosis was confirmed by sequencing, as the enzyme assay was not deficient. Phosphoserine phosphatase deficiency (PSPH) has been reported in a single patient who also had Williams syndrome (Jaeken et al. 1997). The child had growth and psychomotor retardation, but no seizures. His fasting plasma serine levels were low–normal, and his CSF serine levels were low. He was homozygous for a missense mutation that decreased the enzyme activity.

References:

Tabatabaie L, Klomp LW, Berger R et al (2010) L-serine synthesis in the central nervous system: a review on serine defi ciency disorders. Mol Genet Metab 99:256–262
de Koning TJ, Snell K, Duran M et al (2003) l-Serine in disease and development. Biochem J 137:653–661
Hart CE, Race V, Achouri Y et al (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80:931–937
Jaeken J, Detheux M, Fryns JP et al (1997) Phosphoserine phosphatase deficiency in a patient with Williams syndrome. J Med Genet 34: 594–596

Gamma-Aminobutyric Acid (GABA) Disorders

Two disorders affect the catabolism of GABA: GABA transaminase deficiency and succinic semialdehyde dehydrogenase deficiency. GABA transaminase deficiency. Two families have been reported with GABA transaminase deficiency (Jaeken et al. 1984; Tsuji et al. 2010). The patients had axial hypotonia, spasticity, severe convulsions, and feeding problems necessitating tube feeding. Patients in the first family had accelerated growth and increased growth hormone secretion. In the second family, MRI showed diffusion restriction in the internal and external capsule and subcortical white matter areas (Tsuji et al. 2010). Biochemically, patients have an elevation of free GABA in cerebrospinal fluid but also the elevation of homocarnosine and β-alanine. Elevated GABA can be recognized on magnetic resonance spectroscopy (Tsuji et al. 2010). The enzyme activity was deficient in liver and lymphocytes, and mutations were identified in the ABAT gene.

Succinic semialdehyde dehydrogenase deficiency (SSADH) or 4-hydroxybutyric aciduria. Patients with succinic semialdehyde dehydrogenase deficiency accumulate succinic semialdehyde derived from GABA transamination, which is converted by succinic semialdehyde reductase into 4-hydroxybutyric acid and excreted in urine. Most patients present in the first 2 years of life, and whereas 26 % of patients have problems in the neonatal period, an equal number have normal early development (Gibson et al. 1997). These patients present with a static neurological picture of developmental delay and intellectual disability with prominent deficits in expressive language, motor delay, hypotonia, and nonprogressive ataxia, each present in more than 70 % of patients (Gibson et al 1997; Pearl et al. 2003). Neuropsychiatric symptoms are frequent and include hyperactivity, inattention, and anxiety. Sleep disorders are very common and include excessive daytime sleepiness, prolonged REM latency, and reduced REM sleep (Pearl et al. 2009). Seizures are present in 48 % of patients consisting mostly of generalized tonic-clonic and atypical absence seizures and myoclonic seizures in a minority. EEG abnormalities were noted in 26 % of patients. About 10 % of patients have a degenerative course with myoclonus and extrapyramidal movements of chorea and dystonia (Pearl et al. 2009). Neuroimaging shows increased T2 signal intensity in the globus pallidus, cerebellar dentate nucleus and brainstem, and subcortical white matter (Gibson et al. 1997; Pearl et al. 2003). There may also be cerebellar and cerebral atrophy. NMR spectroscopy is usually normal unless special edited sequences for GABA and GABA metabolites are done, which show increases in these compounds (Pearl et al. 2003).

References:

Jaeken J, Casaer P, De Cock P et al (1984) Gamma-aminobutyric acid transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15:165–169
Tsuji M, Aida N, Obata T et al (2010) A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy. J Inherit Metab Dis 33:85–90
Gibson KM, Christensen E, Jakobs C et al (1997) The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics 99:567–574
Pearl PL, Novotny EJ, Acosta MT et al (2003) Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 54(Suppl 6):S73–S80
Pearl PL, Gibson KM, Cortez MA et al (2009) Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis 32:343–352

Co-Chaperon Deficiencies

DNAJC12 encodes a heat shock co-chaperone of the HSP40 family which has been shown to interact with PAH and at least in silico with TH and THPs. Recently, biallelic mutations in the DNAJC12 gene have been identified in six individuals of four families with HPA, serotonin and dopamine deficiency and missing mutations in genes encoding enzymes of neurotransmitter synthesis or pterin metabolism. The affected individuals showed a broad spectrum of clinical symptoms including dystonia, speech delay, axial and limb hypertonia, parkinsonism as well as psychiatric features. Until today, around 20 patients have been described presenting with very mild or even absent neurological symptoms. An additional phenotype with slowly progressing parkinsonism in the presence of mild intellectual disability and no dystonic features at disease onset in adolescence broadens the spectrum of DNAJC12 mutations. In all patients, HPA was detected during NBS. Diagnosis for known primary neurotransmitter deficiencies or BH₄metabolism disorders could not be confirmed by standard procedures. CSF pattern in DNACJ12-D shows decreased 5-HIAA and HVA concentrations with normal or elevated levels of biopterin.

Treatment should be initiated early and consists of administration of the monoamine neurotransmitter precursors L-Dopa/carbidopa and 5-HTP in combination with BH₄supplementation.

This text is an extract from “Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Neuropediatrics 2018; DOI: 10.1055/s-0038-1673630.”

References:

Dekker SL, Kampinga HH, Bergink S. DNAJs: more than substrate delivery to HSPA. Front Mol Biosci. 2015;2:35.
Sarparanta J, Jonson PH, Golzio C, et al. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012;44(4):450-455, S451-452.
Anikster Y, Haack TB, Vilboux T, et al. Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. American Journal of Human Genetics. 2017;100(2):257-266.
Straniero L, Guella I, Cilia R, et al. DNAJC12 and dopa-responsive nonprogressive parkinsonism. Ann Neurol. 2017;82(4):640-646.