Metabolic Brain Disorders

Chapter 228


Metabolic Brain Disorders



Metabolic disorders affecting the brain are relatively common, and clinical signs can range from subtle to severe. This chapter considers selected primary disorders of the brain associated with disturbances of energy metabolism including mitochondrial encephalopathies, inborn errors of metabolism, and methylmalonic aciduria and malonic aciduria.



Energy Metabolism in the Brain


Although the brain represents only 2% of the body weight, it performs many vital functions, even during sleep. Constant high energy production is needed, and any metabolic disorder potentially can have dramatic effects on brain function. Almost all the energy produced and used by the brain is derived from the metabolism of glucose, which is mostly oxidized to CO2 and H2O, with concurrent production of high-energy compounds (see later). Approximately 25% of total body glucose and 20% of total body oxygen consumption (at rest) occurs in the brain. Because glucose is produced or stored only minimally in the brain, the majority must be delivered via the arterial blood flow, with the brain receiving about 15% of the cardiac output. Brain energy metabolism therefore represents an equilibrium between blood flow, glucose utilization, and oxygen consumption.


Cerebral blood flow (CBF), glucose metabolism, and oxygen consumption are closely related. CBF is influenced and regulated by a number of factors, including arterial blood pressure, intracranial pressure, venous outflow, blood viscosity, arterial partial pressures of carbon dioxide (PaCO2) and oxygen (PaO2), collateral flow, vasoreactivity and the status of cerebral autoregulation. Chemical mediators such as K+, Ca2+, H+, and adenosine also may play a role in regulation of CBF. However, cerebral metabolism is the major determinant of regional blood flow. The distribution of capillaries is organized functionally throughout the central nervous system (CNS); hence capillary density may provide an anatomic indicator of oxidative and glucose metabolism. Areas with the greatest capillary density are most commonly located in the gray matter, but regional heterogeneity can be identified. CBF increases with increased neuronal activity. Hemodynamically, CBF is determined by the ratio of cerebral perfusion pressure to cerebral vascular resistance, where cerebral perfusion pressure is the difference between mean arterial blood pressure (MABP) and intracranial pressure (ICP).


High-energy phosphates, predominantly adenosine triphosphate (ATP), are the most important energy source for the brain. ATP is produced almost entirely by oxidative metabolism of glucose. Glucose is derived from the diet and is transported into the brain by transmembrane proteins known as glucose transporters. There glucose undergoes metabolic degradation via glycolysis or the Krebs cycle (tricarboxylic acid cycle); these processes generate 2 and 36 molecules of ATP, respectively. Glycolysis also leads to the production of pyruvate, which can follow three different pathways: (1) it can be metabolized to ethanol (alcoholic fermentation); (2) it can be reduced to lactate (lactic fermentation); or (3) it can be transferred to the mitochondria, where it is used in the tricarboxylic acid cycle. Most of the energy obtained from the tricarboxylic acid cycle is captured by the oxidized form of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, and later converted to ATP via an electron transport chain in mitochondria, known as oxidative phosphorylation.


Most of the ATP (~65%) is used to maintain energy-dependent ion transport—in particular, the Na+,K+-ATPase pump—which represents the main energy-consuming process in neural cells. The remaining energy is used for axonal transport and for the synthesis of neurotransmitters, proteins, lipids, and glycogen. Despite that only small quantities of neurotransmitters are stored in the brain, neurotransmitter synthesis actually can account for about 5% of the energy consumption, and it takes place almost entirely in the glial cells. Although brain energy metabolism often is considered to reflect predominantly neuronal energy metabolism, it is now clear that other cell types—namely, neuroglial and vascular endothelial cells—not only consume energy but also can play an active role in the flux of energy substrates to neurons. Glial cells, which make up almost 50% of the brain volume, have a much lower metabolic rate than neurons and account for less than 10% of total cerebral metabolism. Among the glial cells, astrocytes seem mainly to contribute to brain energy metabolism. Moreover, other energy substrates such as lactate and pyruvate can be released by astrocytes, and they can potentially be used to a lesser degree to support the metabolism of neurons.


Brain function and tissue integrity also are highly dependent on a continuous supply of oxygen. Changes in local brain energy metabolism now can be studied in humans using functional magnetic resonance imaging (MRI) and positron emission tomography (PET). These studies can monitor alterations in the relationships between blood flow, glucose utilization, and oxygen consumption during activation of specific brain areas.


In addition to oxygen supply, clearance of carbon dioxide also is very important. Minimal changes in PaCO2 can have a marked impact on cerebral blood flow by changing the hydrogen ion concentration and then modulating extracellular pH. This can modify the cerebrovascular resistance and blood flow. Of importance to clinicians, hypercapnia relaxes vascular smooth muscles, whereas hypocapnia produces vasoconstriction and reduces flow.


Disruption of blood flow, glucose utilization, oxygen supply, and clearance of metabolites all potentially can lead to metabolic encephalopathy. Metabolic encephalopathies can be divided into either primary or secondary, depending on whether the encephalopathy is due to a local metabolic disorder or a systemic disease, respectively. Systemic diseases that can cause a secondary metabolic encephalopathy, including those associated with hepatic, renal, and cardiovascular diseases as well as hypoglycemia, electrolyte disorders, and acid-base disturbances, are beyond the scope of this chapter. The focus here is on those brain diseases that are caused primarily by abnormal cellular metabolism or abnormal function of the mitochondrial respiratory chain.



Primary Metabolic Brain Diseases


Primary metabolic brain disorders are the direct result of a defect in cellular metabolism, caused by deficiencies of either mitochondrial respiratory chain enzymes or, less commonly, cytosolic enzymes. This group of diseases usually is referred to as mitochondrial encephalopathy. In addition, encephalopathies due to an abnormal metabolism of organic and amino acids are discussed briefly at the end of the chapter.



Mitochondrial Encephalopathies


Mitochondria are organelles located in the cytoplasm of almost all mammalian cells and they are inherited maternally. Because several important biochemical functions take place in mitochondria, such as the tricarboxylic acid cycle and oxidative phosphorylation as described earlier, defects in the respiratory chain complexes can lead to different metabolic disorders. Most of these defects are heritable and are the result of either a nuclear DNA or a mitochondrial DNA mutation (with mitochondrial DNA being of maternal inheritance). The clinical expression of a mitochondrial DNA mutation is heterogeneous. Tissues with high metabolic demand such as brain, heart, and muscle are more prone to develop dysfunction. Although pure neurologic syndromes involving either the central nervous system (CNS) or peripheral nervous system (PNS) are possible, multisystemic disorders are not uncommon. Different syndromes can be associated with the same mutation, and a single syndrome can be associated with different mutations.


In humans, many mitochondrial encephalopathies, myelopathies, and myopathies have been reported. Recently, several inherited myopathies, mitochondrial encephalopathies, and encephalomyelopathies have been reported in dogs.



Clinical Signs


In humans with mitochondrial encephalopathy, severity can vary from acute life-threatening disease to a subacute progressive degenerative disorder. Progression may be unrelenting with rapid deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades. The presenting clinical signs of these neurometabolic diseases often are very non specific and are caused by progressive destruction of motor, mental, and perceptual functions potentially associated with seizures and with earlier death, often before adulthood.


As in people, relatively nonspecific, progressive or episodic, classically life-threatening signs of CNS dysfunction related to neurometabolic diseases have been reported in isolated cases or families of dogs (Table 228-1). Since the neurons have the highest metabolic demand of the different brain cells, the cerebral cortex is the most susceptible to energy metabolism disorders. Thus the overwhelming majority of animals with metabolic encephalopathies initially experience neurologic signs referable to forebrain dysfunction; these signs then can progress to more generalized brain involvement (brainstem or cerebellar signs may develop later on) and eventually death. The neurologic signs usually develop in the first year of life; however, the age of onset may vary from as young as 4 months to 6 years or older. Clinical signs usually are compatible with a generalized bilateral and symmetric encephalopathy or a multifocal CNS disease (e.g., cerebrum and cerebellum, or cerebrum and spinal cord).



TABLE 228-1


Clinical Signs and Imaging Findings in Dogs with Mitochondrial Encephalopathy



































Breed Clinical Signs Imaging Findings
Alaskan husky Ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulty in prehension of food MRI: Bilateral lesions in center of brainstem, extending from midthalamus to medulla; to a lesser degree, lesions in putamen, caudate nucleus, and claustrum. Lesions were hyperintense with T2 weighting and isointense/hypointense nonenhancing with T1 weighting.
Yorkshire terrier Behavioral changes with or without seizures, visual deficits, generalized ataxia Well-circumscribed, noncontiguous, bilateral, oblique areas within basal nuclei, midthalamus and brainstem that appeared hypodense on CT and on MRI images; hyperintense with T2 weighting and hypointense nonenhancing with T1 weighting.
Jack Russell terrier Ataxia/hypermetria, fine head tremor, bilateral blindness and deafness Imaging not performed.
English springer spaniel Ataxia/hypermetria, visual deficits, positional nystagmus, delayed postural reactions in all four limbs Imaging not performed.
Shih Tzu Progressive bilateral brachial plexus/caudal cervical spinal cord disorder; later, brain signs (behavioral changes such as aggressiveness and vocalization) MRI: Two well-demarcated, intraaxial lesions into cervical spinal cord, caudal colliculi, vestibular nuclei, medulla of cerebellum; hyperintense with T2 weighting and FLAIR, and hypointense nonenhancing with T1 weighting.
Australian cattle dog Seizures, followed by progressive ataxia and tetraparesis MRI: Multiple ovoid, bilaterally symmetric, T2 hyperintense, T1 isointense/hypointense nonenhancing lesions on interposital nuclei, vestibular nuclei, pontine nuclei, and caudal colliculi.
Shetland sheepdog and Australian cattle dog Seizures, followed by depressed mental status, hypermetric gait, intention head and neck tremor, and eventually inability to walk with extensor spasticity of all four limbs CT: Diffuse hypomyelination (i.e., hypodense areas) and dilated lateral and fourth ventricles.

CT, Computed tomography; FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging.


Clinical signs generally correlate well with the location of structural lesions observed on gross and microscopic examination of the CNS. However, the abnormalities also may reflect a functional disturbance of neuronal populations not visible by light microscopy, and this is relatively common in metabolic disorders. In cases of forebrain localization, mental obtundation, blindness, and behavioral changes with or without seizures have been reported most commonly. Brainstem-cerebellar signs such as generalized ataxia, dysmetria, and a wide-based stance also have been reported with a relatively high frequency. A combination of these signs is seen with a diffuse or multifocal problem.


Encephalopathies proved or suspected to be due to a mitochondrial disorder have been reported sporadically in Alaskan huskies, Yorkshire terriers, Jack Russell terriers, springer spaniels, Shih Tzus, Australian cattle dogs, and Shetland sheepdogs. However, other dogs previously reported to have vacuolar or spongiform encephalopathy of idiopathic origin currently are suspected to have an underlying mitochondrial dysfunction. The encephalopathy described in the Alaskan husky shares many similarities with that reported in the Yorkshire terrier, springer spaniel, and, to a lesser degree, the Jack Russell terrier and resembles subacute necrotizing encephalomyelopathy, or Leigh’s syndrome, in humans. This syndrome includes a heterogeneous group of heritable neurodegenerative diseases. Currently, most of the diseases reported are known to be caused by diverse defects of the mitochondrial respiratory chain.


In dogs with changes similar to those in Leigh’s syndrome, the clinical signs usually include ataxia (mostly cerebellar-quality ataxia), seizures, behavioral abnormalities (including obtundation and propulsive pacing), and visual deficits. Moreover, the neurologic examination commonly reveals delayed postural reactions and some other cerebellovestibular signs like nystagmus and head tremor. Varying degrees of tetraparesis, facial hypalgesia, and difficulty in prehending food also have been reported in Alaskan huskies.


In Australian cattle dogs, after an initial presentation of psychomotor seizures (episodes of running in circles, vocalizing, and urinating), usually progressive fatigue and thoracic limb stiffness, and eventually spastic tetraparesis occur over a 6- to 12-month period (Harkin et al, 1999; Brenner et al, 1997b). In one dog, the thoracic limb stiffness was exacerbated while the dog was placed in lateral recumbency; the thoracic limbs were in fact rigidly extended in a tetanic posture with persistent contraction of extensor muscles (Harkin et al, 1999). In the single Shih Tzu recently reported in which a mitochondrial CNS disease was suspected, the signs initially were compatible with a progressive bilateral brachial plexus–caudal cervical spinal cord disorder that mostly spared the back legs; only later did the dog develop concurrent brain signs consisting of behavioral changes such as aggressiveness and vocalization (Kent et al, 2009). In the Shetland sheepdogs the clinical signs were intermittent, present from puppyhood, and composed mainly of seizures. As the disease progressed, depressed mental status, hypermetric gait, and intention head and neck tremor developed, and ultimately these dogs became unable to walk, with extensor spasticity of all four limbs (Wood et al, 2001).

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Metabolic Brain Disorders

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