Pelizaeus-Merzbacher disease (PMD) is a recessive X chromosome-linked disorder that occurs in 1:200,000 to 1:500,000 males. The disease is characterized by hypomyelination of the central nervous system, leading to neurologic symptoms such as abnormal muscle tone (hypotonia in newborns and muscle spasticity in children), ataxia, nystagmus, psychomotor retardation seizures, and stridor [3]. PMD children die early due to respiratory complications such as aspiration pneumonia [3, 4]. Patients often suffer from joint contractures, which may require surgery. Anaesthetic evidence is restricted to case reports. Aspiration pneumonia, epilepsy, and gastroesophageal reflux disease must be considered preoperatively, and airway complications, exacerbation of spasticity, and seizures must be considered postoperatively [5].

Homocystinuria type III is inherited as an autosomal recessive that affects the metabolism of methionine. It is caused by a tetrahydrofolate reductase deficiency and has a prevalence of 1:200,000 to 1:335,000. In contrast, type I results from deficient pyridoxine and cystathionine synthase, and type II results from a defective tetrahydrofolate methyltransferase.

Type III patients suffer from delayed motor development, psychiatric diseases, and seizures. The lack of methionine and concomitant high serum homocysteine levels can cause thromboembolic complications perioperatively. Also, perioperative neurological impairment has been described in association with the use of nitrous oxide [6]. Case reports such as by Yamada et al. recommend the use of prophylactic aspirin, heparin, and pneumatic foot compression systems to prevent thromboembolic complications perioperatively [6]. Nitrous oxide must not be applied [7–9]. Eschweiler et al. described the possibility of postoperative psychosis in such patients since oxidation products of homocysteine are robust glutamate agonists and affect central glutamatergic transmission [10].

Hyperhomocysteinaemia is a related disorder often presents with coronary artery disease and concomitant limited myocardial function as well as increased thrombotic events [11]. Aggarwal et al. stress the importance of reducing homocysteine levels and applying traditional prophylactic measures perioperatively to minimize the risk of thrombotic complications [11]. The risk for thromboembolic complications, and the accompanying probable need for anticoagulation, may contraindicate neuraxial anaesthesia [12].

The Lesch-Nyhan syndrome is a recessive, X chromosome-linked hypoxanthine-guanine phosphoribosyltransferase deficiency, which results in high purine levels and concomitant uric acidosis. It affects 1:380,000 males. Patients suffer from intellectual disability and present classical self-mutilation and musculoskeletal abnormalities including dysphagia, spasticity, and impaired drug metabolism [13]. Additionally, hyperuricemia causes renal dysfunction, which progresses to lethal renal failure. Three dimensions were described for consideration by anaesthesiologists: First, perioral scars derived from self-mutilation can cause a difficult intubation anatomy, and gastric reflux must be anticipated; second, seizures are common and must be recognized under general anaesthesia; and third, patients may show renal insufficiency caused by uric acidosis [14]. Overall, drug metabolism is impaired, but etomidate, ketamine, and thiopental are safe, whereas benzodiazepines and opioids must be used with caution [14].

Mucolipidosis II is a lysosomal storage disease of the nervous system caused by a deficient N-acetylglucosamine-1-phosphotransferase. It is an autosomal recessive disease with an incidence of 1:100,000 to 1:400,000. The deficiency results in exocytosis of lysosomal enzymes rather than physiological sequestration in intracellular lysosomes. One consequence is that mucolipids and other macromolecules concentrate to toxic levels in lysosomes [15]. Usual clinical findings include both mental and physical disabilities and orofacial abnormalities. For anaesthesiologists, the main concerns are difficult airway anatomy due to facial dysmorphia, large tongue, restricted cervical movement, and hypertrophic adenoids and tonsils. Additionally, coronary artery atresia and consecutive acute heart failure have been described [16], whereas no pharmacological risks have been reported [17].

The oculocerebrorenal syndrome (Lowe syndrome) is an X chromosome-linked multisystem disorder of amino acid transport with an incidence of 1:500,000. It causes hepatic and polyuric renal insufficiency with organic aciduria, hydrophthalmos, intellectual disability, growth failure, easy fatigability, ocular abnormalities, and orthopaedic abnormalities; for the later, patients often need surgery [18, 19]. Intellectual disabilities are thought to be caused by white matter destruction, which is also thought to account for significant seizures [20]. Renal acidosis and hypokalaemia with associated cardiac side effects were described as the main issues for concern by anaesthesiologists [21]. As Saricaog̬lu et al. point out, the acidosis facilitates passage of opioids across the blood-brain barrier, leading to deeper sedation and depressed reflexes, which increases the risk for pulmonary aspiration perioperatively [21]. Perioperative correction of electrolyte imbalances and differentiated fluid management is of essence. Retrognathia is frequently observed; thus, careful airway management is mandatory as is the use of muscle relaxants due to both muscular weakness and electrolyte imbalances [22].

Carbamoyl-phosphate synthetase I deficiency causes hyperammonaemia. It is an autosomal recessive disease with an incidence of 1:800,000. During surgical stress under general anaesthesia or in metabolic distress, ammonia levels can increase dramatically in these patients, causing cerebral oedema and concomitant brain herniation. Regional anaesthesia and sedation are recommended to ensure sufficient control of cerebral function [23].

Hyperargininaemia/arginase deficiency is an autosomal recessive disorder of the urea cycle with an incidence of 1:300,000. Patients are affected by psychomotor retardation, seizures, and progressive spastic quadriparesis [24]. Kaul et al. described four major anaesthesia-associated risks threatening patients: Patients are at risk of hyperammonaemic cerebral oedema and severe hypotension upon induction of general anaesthesia because arginine stimulates vasodilatation. Aggressive perioperative fluid administration can counter the latter but increases the risk of the former. Additionally, patients are at risk for seizures, and volatile anaesthetics may trigger an epileptic crisis; potentially significant paresis increases the risk of unpredictable action of depolarizing and non-depolarizing muscle relaxants. To avoid the need for the muscle relaxants, the use of laryngeal masks in such patients is suggested [25].

Overall, patients with rare inborn metabolic brain diseases can present with psychomotor retardation, epilepsy, and abnormal muscle tone. Accordingly, impaired cognition, seizures, and associated respiratory complications, such as aspiration, should be anticipated. Orofacial abnormalities can cause difficult intubation. Drug metabolism can be impaired; therefore, specific caution is required when applying benzodiazepines, muscle relaxants, and opioids.

Cockayne syndrome (also known as Weber-Cockayne syndrome or Neill-Dingwall syndrome) is an autosomal recessive progeria resulting from a nucleotide excision repair deficiency. It has an incidence of 1:500,000. Clinically, patients present facial dysmorphias, microcephaly and cerebral atrophy, concomitant intellectual deficiency, and delayed growth. A few cases have been studied specifically for perioperative considerations, such as potentially difficult establishment of a safe airway upon induction of general anaesthesia. Because of the risk of haemodynamic instability resulting from administration of hypnotics, Tsukamoto et al. recommend not relying on haemodynamics to measure the depth of anaesthesia in patients with premature ageing, but recommend use of EEG devices such as BIS monitors as employed with geriatric patients [26].

Xeroderma pigmentosum is an autosomal recessive defect in a DNA repair mechanism. It has an incidence of 1:250:000. Although several subtypes have been described, all patients lack mechanisms for skin repair after actinic stress. Some subtypes additionally include neurological deficiencies, and patients usually die within their first decade of life. Guidelines to treat such patients perioperatively are lacking; however, some reports suggest that volatile anaesthetics worsen neurological symptoms and should not be used [27–29]. A Nepalese case series warned against potentially difficult airway scenarios upon induction of general anaesthesia and recommended avoiding muscle relaxants due to their potentially unpredictable effect. Additionally, both benzodiazepines and opioids can show a pronounced synergistic effect in patients with neurologic disabilities [30].

Overall, patients with rare DNA repair-deficiency disorders can present with intellectual disabilities, retarded growth, and orofacial abnormalities. Establishment of a safe airway may be complicated, and drug metabolism can be affected; thus, specific caution is required when using benzodiazepines, muscle relaxants, or opioids.

Barth syndrome is an X chromosome-linked disease, which leads to elevated excretion of 3-methylglutaconic acid. It has an incidence of 1:300,000. The clinical presentation of Barth syndrome is highly variable, manifesting as a multisystem disease including cardiomyopathies and concomitant heart failure, growth retardation, muscle weakness, and cyclic neutropenia [31]. Perioperatively, careful cardiocirculatory monitoring is essential, and neuromuscular blockers may cause problems due to their unpredictable kinetics and dynamics.

Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by absence of adipose tissue and insulin resistance; every second patient suffers from intellectual disability. It has an incidence of 1:500,000. Clinically, patients exhibit an athletic appearance, but present with an anabolic syndrome including hypertrophic cardiomyopathy, advanced bone age, sexual precocity, macroglossia, and tonsillar hyperplasia [32]. Perioperative essentials include the management of hypertrophic cardiomyopathy and recognition of probable difficulties in establishing a safe airway access [32]. Bennett et al. encourage short-acting agents and consideration of possible delayed emergence from sevoflurane anaesthesia due to lack of adipose tissue in the central nervous system and concomitant disproportional effects of fat-soluble agents [32].

Overall, patients with rare lipid metabolism disorders can present with cardiomyopathies, concomitant heart failure, intellectual disabilities, and retarded growth. Specific caution must be given when using volatile anaesthetics, benzodiazepines, muscle relaxants, and opioids. Short-acting agents should be considered.

Isovaleric acidaemia is an autosomal recessive error in amino acid metabolism in which a deficient isovaleryl-CoA dehydrogenase leads to disorders in leucine metabolism. It affects 1:250,000. Under perioperative stress, an increase in plasma levels of isovaleryl-CoA metabolites can cause severe glucose disturbances, hyperammonaemia, hypocalcaemia, and non-anion gap metabolic acidosis [33]. Anaesthesiologists must aim to prevent metabolic crises by supporting anabolism (e.g. with sugar) and simultaneously reducing leucine intake. Additionally, both production and accumulation of isovaleryl-CoA from leucine metabolism must be reduced with a carnitine and glycine diet [33, 34].